The 1540s decade ran from January 1, 1540, to December 31, 1549.
- January – Dunstable Priory falls prey to Henry VIII of England's Dissolution of the Monasteries.
- January 6 – King Henry VIII of England marries Anne of Cleves, his fourth Queen consort. The marriage lasts six months and ends in divorce in July.
- February 14 – Charles V, Holy Roman Emperor, enters Ghent without resistance, and executes the rebels.
- March – Waltham Abbey is the final priory to fall prey to the Dissolution of the Monasteries.
- May 17 – Battle of Kannauj: Sher Shah Suri defeats and deposes Mughal Emperor Humayan, establishing the Sur Empire.
- July 7 – Coronado captures Hawikuh, at this time known as part of Cíbola, but fails to find the legendary gold.
- July 9 – King Henry VIII of England divorces Anne of Cleves, his fourth Queen consort.
- July 28 – One of the most important political figures of the reign of Henry VIII of England, Thomas Cromwell, is executed on order from the king, on charges of treason. Henry marries his fifth wife, Catherine Howard, on the same day.
- August 15 – In Peru, the Spanish captain Garcí Manuel de Carbajal founded the Villa Hermosa de Arequipa, and one year after, Charles V of Germany and I of Spain gave the valley a status of 'city' by Royal Decree.
- September – Gibraltar is sacked by the fleet of Barbary pirate Ali Hamet, a Sardinian renegade in the service of the Ottoman Empire, and many of its leading citizens are taken as captives to Peñón de Vélez de la Gomera in Morocco. This leads to construction of the defensive Charles V Wall, at this time known as the Muralla de San Benito.
- September 3 – Gelawdewos succeeds his father Lebna Dengel, as Emperor of Ethiopia.
- September 27 – The Society of Jesus (Jesuits) is approved by Pope Paul III, in his bull Regimini militantis Ecclesiae.
- October 1 – Battle of Alborán: A Habsburg Spanish fleet, under the command of Bernardino de Mendoza, destroys an Ottoman fleet, commanded by Ali Hamet, off Alborán Island in the Mediterranean.
- October 18 – An expedition led by Spanish conquistador Hernando de Soto destroys the fortified village of Mabila in modern-day Alabama, killing paramount chief Tuskaloosa.
- Antwerp is besieged for three days, by Maarten van Rossum.
- Georg Joachim Rheticus publishes De libris revolutionum Copernici narratio prima in Danzig, an abstract of Copernicus' as yet unpublished De revolutionibus orbium coelestium, and the first printed publication of Copernican heliocentrism.
- Europe is hit by a heat wave and drought lasting for about seven months. Rivers such as the Rhine and Seine dry up, and many people die from dysentery and other illnesses, caused by lack of safe drinking water. However, this year's vintage from Würzburger Stein and other vineyards is particularly notable.
- Martin Luther expels theologian Caspar Schwenckfeld from Silesia.
- Paracelsus visits Villach.
- approximate date – The musket is introduced into Japan from Europe.
- February 12 – Pedro de Valdivia founds Santiago del Nuevo Extremo, which will become the capital of Chile.
- April 7 – Francis Xavier leaves Lisbon, on a mission to the Portuguese East Indies.
- April 24 – Battle of Sahart: The Emperor of Ethiopia defeats by the forces of Imam Ahmad Gragn.
- May 8 – Spanish explorer Hernando de Soto reaches the Mississippi River, naming it the Rio de Espiritu Santo ("River of the Holy Spirit").
- May 23 – Jacques Cartier departs from Saint-Malo, France on his third voyage.
- June 18 – By the Crown of Ireland Act, the Parliament of Ireland declares King Henry VIII of England and his heirs to be Kings of Ireland, replacing the Lordship of Ireland with the Kingdom of Ireland.
- July 9 – Estêvão da Gama departs Massawa, leaving behind 400 matchlock men and 150 slaves under his brother Cristóvão da Gama, with orders to assist the Emperor of Ethiopia to defeat Ahmad ibn Ibrahim al-Ghazi, who has invaded his Empire.
- August 29 – The Janissaries of Suleiman the Magnificent take Buda by ruse, hiding themselves as visitors.
- September 9–11 – Spanish noblewoman Beatriz de la Cueva serves as governor of the colony of Guatemala, before she is killed in a mudslide from Volcán de Agua, which ruins the capital city, Ciudad Vieja.
- September 13 – After three years of exile, John Calvin returns to Geneva to reform the church under a body of doctrine that comes to be known as Calvinism.
- October – An Algerian military campaign by Charles V of Spain (Habsburg) is unsuccessful.
- December 10 – Thomas Culpeper and Francis Dereham are executed for having affairs with Catherine Howard, Queen of England and wife of Henry VIII.
- The Portuguese defeat the Muslims near Lake Tana.
- Ottoman Sultan Suleiman the Magnificent seals off The Golden Gate in Jerusalem.
- Iceland adopts the Lutheran faith.
- Gerardus Mercator makes his first globe.
- The first official translation of the entire Bible into Swedish is made.
- John Calvin translates his Institutio Christianae religionis into French, as L'Institution chrétienne.
- Elia Levita's chivalric romance, the Bovo-Bukh, is first printed, the earliest published secular work in Yiddish.
- February 2 – Battle of Baçente: The Portuguese under Cristóvão da Gama capture a Moslem-occupied hillfort in northern Ethiopia.
- February 13 – Catherine Howard, the fifth wife of Henry VIII of England, is executed for adultery.
- February 14 – Guadalajara, Mexico, is founded by the Spaniards after three previous attempts failed, due to aggressive opposition from local tribes.
- March 8 – Antoine Escalin des Eymars, the French ambassador, returns from Constantinople, with promises of Ottoman aid in a war against Charles V, Holy Roman Emperor.
- March – Renyin palace rebellion: A group of Ming dynasty palace women fail to murder the Jiajing Emperor and are executed by slow-slicing.
- April 4–16 – Battle of Jarte in Ethiopia: The Portuguese under Cristóvão da Gama encounter the army of Imam Ahmad Gragn, and inflict upon him two successive defeats.
- May 19 – The Prome Kingdom, in modern-day central Burma, is conquered by the Taungoo Dynasty.
- July 12 – Charles V, Holy Roman Emperor declares war on King Francis I of France. This time King Henry VIII of England is allied to the Emperor, while James V of Scotland and Sultan Suleiman I are allied to the French.
- August – Battle of the Hill of the Jews: During the rainy season, Cristóvão da Gama captures a strategic position and many badly-needed horses.
- August 24 – Battle of Haddon Rig: Scotland defeats England.
- August 27 – Citizens of Hildesheim in the Holy Roman Empire profess themselves to the Lutheran teachings. As a pledge owner, the city provides for the carrying out of the Protestant Reformation in the city and Peine. Priests from the localities of Clauen, Hohenhameln, Soßmar, Schmedenstedt, Lengede and Rosenthal resume their offices in the interest of the Reformation.
- August 28 – Battle of Wofla in Ethiopia: Reinforced with at least 600 arquebusiers and cavalry, Imam Ahmad Gragn attacks the Portuguese camp. The Portuguese are scattered; Cristóvão da Gama is captured and executed.
- September 4 – The earliest recorded Preston Guild Court is held in Lancashire, England, in the modern sequence, which lasts unbroken until 1922.
- September 28 – Portuguese explorer Juan Rodríguez Cabrillo lands in what is now San Diego Bay, and names it "San Miguel"; it will later become the city of San Diego.
- October 7 – Cabrillo becomes the first European to set foot on Santa Catalina Island, California.
- November 24 – Battle of Solway Moss: An English army invades Scotland, and defeats a Scottish army.
- December 14 – Mary, Queen of Scots, becomes queen regnant one week after the death of her father, James V of Scotland.
- The first contact of Japan with the West occurs when a Portuguese ship, blown off its course to China, lands Fernão Mendes Pinto, Francisco Zeimoto and António Mota in Japan. (some sources say 1543).
- Pope Paul III establishes the Holy Office, with jurisdiction over the Roman Inquisition.
- Bartolomé de las Casas completes A Short Account of the Destruction of the Indies, which will be published in 1552.
- February 11 – King Henry VIII of England allies with Charles V, Holy Roman Emperor, against France.
- February 21 – Battle of Wayna Daga: A joint Ethiopian-Portuguese force of 8,500, under Emperor Gelawdewos of Ethiopia, defeats Imam Ahmad ibn Ibrahim al-Ghazi's army of over 14,000, ending the Ethiopian–Adal war.
- King Gustav Vasa's troops crush the forces of Swedish peasant rebel Nils Dacke in battle, ending the uprising. Dacke escapes, but is captured and killed in the summer.
- Consolidating Act of Welsh Union: The Parliament of England establishes counties and regularises parliamentary representation in Wales.
- April – Campaign of Suleiman: Suleiman the Magnificent, Ottoman Sultan, revives the Little War in Hungary.
- May – Nicolaus Copernicus publishes De revolutionibus orbium coelestium (On the Revolutions of the Heavenly Spheres) in Nuremberg, offering mathematical arguments for the existence of the heliocentric universe, denying the geocentric model. Copernicus dies on May 24 in Frombork, at the age of 70.
- June – Andreas Vesalius publishes De humani corporis fabrica (On the Fabric of the Human Body), revolutionising the science of human anatomy.
- July 1 – The Treaty of Greenwich is signed between England and Scotland (repudiated by Scotland December 11).
- July 12 – King Henry VIII of England marries Catherine Parr. It is the sixth and last of Henry's marriages and the third of Catherine's. Princess Elizabeth attends the wedding. This month, the Parliament of England passes the Third Succession Act, restoring the Princesses Mary and Elizabeth, Henry's daughters, to the line of succession to the English throne.
- July 25 – August 10 – Siege of Esztergom: Suleiman the Magnificent, Ottoman Sultan, besieges and takes Esztergom in Hungary.
- August 6–22 – Siege of Nice: Ottoman Empire and French forces (under the Franco-Ottoman alliance), led by Admiral Hayreddin Barbarossa, besiege and take Nice.
- August 25 – Led by the Chinese pirate Wang Zhi, the first Europeans and firearms arrive in Japan in Tanegashima island in southern Kyushu including Portuguese traders António Mota, Antonio Peixoto, Francisco Zeimoto, and presumably Fernão Mendes Pinto
- September–October – Landrecies in Picardy is besieged by forces under Charles V, Holy Roman Emperor, but the siege is withdrawn on the approach of the French army.
- September – Campaign of Suleiman: Suleiman the Magnificent captures the Hungarian coronation city of Székesfehérvár. The city will be occupied by the Ottoman Empire for 145 years.
- September 9 – Mary Stuart is crowned the Queen of Scots in Stirling at nine months old.
- Martin Luther publishes On the Jews and Their Lies.
- Mikael Agricola publishes Abckiria.
- The Lighthouse of Genoa is completed in present form.
- Indians in the Spanish Empire are declared free, against the wishes of local settlers.
- January 13 – At Västerås, the estates of Sweden swear loyalty to King Gustav Vasa and to his heirs, ending the traditional electoral monarchy in Sweden. Gustav subsequently signs an alliance with the Kingdom of France.
- February 20 – Fourth Diet of Speyer is convened.
- April 11 – Battle of Ceresole: French forces under the Comte d'Enghien defeat forces of the Holy Roman Empire, under the Marques Del Vasto, near Turin.
- May – Charles V, Holy Roman Emperor, again invades eastern France.
- May 3 – Edward Seymour, Earl of Hertford, with an English army, captures Leith and Edinburgh from the Kingdom of Scotland.
- June 19–August 18 – Troops of the Holy Roman Empire besiege Saint-Dizier, in eastern France.
- July – Battle of the Shirts: The Clan Fraser of Lovat and Macdonalds of Clan Ranald fight over a disputed chiefship in Scotland; reportedly, five Frasers and eight Macdonalds survive.
- July 19–September 14 – Italian War of 1542–46 – First Siege of Boulogne: King Henry VIII of England besieges and captures Boulogne in northern France.
- August 17 – The University of Königsberg ("Albertina") is inaugurated (founding deed signed July 20 by Albert, Duke of Prussia).
- September 18 – Peace of Crépy: Peace is declared between Charles V, Holy Roman Emperor, and Francis I of France. The war between France and England continues.
- September 22 – Captain Juan Bautista Pastene leads the first European expedition to the estuary of Valdivia, Chile and Corral Bay.
- October 9 – Second Siege of Boulogne: French forces under the Dauphin assault Boulogne, but are ultimately unsuccessful.
- Mongols burn the suburbs of Peking in China.
- The Orto botanico di Pisa botanical garden is established by Cosimo I de' Medici, Grand Duke of Tuscany, in Italy, under the direction of botanist Luca Ghini, who also creates the first herbarium.
- Rats make their first appearance in North America.
- Portuguese explorers encounter the island of Taiwan, and call it Ilha Formosa ("Beautiful Island").[verification needed]
- February 22 – A firman of the Ottoman Empire is issued for the dethronement of Radu Paisie as Prince of Wallachia.
- February 27 – Battle of Ancrum Moor: The Scots are victorious over numerically superior English forces.
- April 1 – Potosí is founded by the Spanish as a mining town after the discovery of huge silver deposits in this area of modern-day Bolivia. Silver mined from Huayna Potosí Mountain provides most of the wealth on which the Spanish Empire is based until its fall in the early 19th century.
- June 13 – Spanish explorer Yñigo Ortiz de Retez sets out to navigate the northern coast of New Guinea.
- July 18–19 – Battle of the Solent between the English and French fleets: The engagement is inconclusive, but on the second day Henry VIII of England's flagship, the Mary Rose, sinks.
- c. July 21 – Italian Wars: Battle of Bonchurch – The English reverse an attempted French invasion of the Isle of Wight, off the coast of England.
- c. September – Mobye Narapati succeeds as ruler of the Ava Kingdom and offers peace to the Taungoo Dynasty, ending the Taungoo–Ava War (1538–45), and leaving the Taungoo as the dominant rulers in Burma.
- October – The Siege of Kawagoe Castle begins, as part of an unsuccessful attempt by the Uesugi clan to regain Kawagoe Castle from the Late Hōjō clan in Japan.
- December 13 – The Council of Trent officially opens in northern Italy (closes 1563).
- Battle of Sokhoista: The army of the Ottoman Empire defeats an alliance of Georgian dynasts.
- Diogo I Nkumbi a Mpudi overthrows his uncle Pedro I of Kongo to become manikongo.
- In China, a large failure of the harvest in Henan province occurs due to excessive rainfall, which drives up the price of wheat, and forces many to flee their rural counties; those who stay behind are forced to survive by eating leaves, bark, and human flesh.
- In the territory of New Spain in modern-day Mexico, the Cocoliztli Epidemic of 1545–1548 begins.
- St. Anne's Church, Augsburg converts to Lutheranism.
- May 19 – The Siege of Kawagoe Castle ends in defeat for the Uesugi clan, in their attempt to regain Kawagoe Castle from the Late Hōjō clan in Japan.
- June 7 – The Treaty of Ardres (also known as the Treaty of Camp) is signed, resulting in peace between the kingdoms of England and France, ending the Italian War of 1542–1546.
- July 10 – The Schmalkaldic War, a political struggle between imperial forces under Charles V, Holy Roman Emperor, and the Lutheran forces of the Schmalkaldic League, begins.
- November 4 – Christ Church, Oxford, is refounded as a college by Henry VIII of England under this name.
- December 19 – Trinity College, Cambridge, is founded by Henry VIII of England.
- Katharina von Bora flees to Magdeburg.
- Michelangelo is made chief architect of St. Peter's Basilica in Rome.
- The Spanish conquest of Yucatán is completed.
- January 8 – The first Lithuanian-language book, Simple Words of Catechism, is published in Königsberg by Martynas Mažvydas.
- January 13 – Henry Howard, Earl of Surrey is sentenced to death.
- January 16 – Grand Duke Ivan IV of Muscovy becomes the first Tsar of Russia, replacing the 264-year-old Grand Duchy of Moscow with the Tsardom of Russia.
- January 28 – King Henry VIII of England dies in London and is succeeded by his 9-year-old son Edward VI as King of England.
- February 20 – Edward VI of England is crowned at Westminster Abbey.
- March 31 – King Francis I of France dies at the Château de Rambouillet and is succeeded by his eldest surviving son Henry II (on his 28th birthday) as King of France.
- April 4 – Catherine Parr, widow of King Henry VIII of England, secretly marries Thomas Seymour, 1st Baron Seymour of Sudeley.
- April 24 – Battle of Mühlberg: Emperor Charles V defeats the Lutheran forces of the Schmalkaldic League.
- August 13 – The Duchy of Brittany unites with the Kingdom of France.
- September 10 – Battle of Pinkie Cleugh: An English army under the Duke of Somerset, Lord Protector of England, defeats a Scottish army under James Hamilton, 2nd Earl of Arran, the Regent. The English seize Edinburgh.
- Huguenots increasingly immigrate to the English county of Kent, especially Canterbury.
- The Chambre Ardente is established in Paris for trying heretics.
- Work on construction of the Château de Chambord, in the Loire Valley, for Francis I of France, ceases.
- John Dee visits the Low Countries, to study navigation with Gemma Frisius.
- Edward VI of England outlaws execution by boiling.
- February 14 – Battle of Uedahara: Firearms are used for the first time on the battlefield in Japan, and Takeda Shingen is defeated by Murakami Yoshikiyo.
- April 1 – Sigismund II Augustus succeeds his father, Sigismund I the Old, as King of Poland and Grand Duke of Lithuania.
- May 11 – Start of the great fire in Brielle.
- June – Ming Chinese naval forces commanded by Zhu Wan destroy the pirate haven of Shuangyu, frequented by Chinese, Japanese, and Portuguese smugglers.
- July 7 – A marriage treaty is signed between Scotland and France, whereby five-year-old Mary, Queen of Scots, is betrothed to the future King Francis II of France.
- August 7 – Mary, Queen of Scots, leaves for France.
- October 20 – The city of La Paz, Bolivia, is founded.
- October 31 – At the first sejm of King Sigismund II Augustus of Poland, deputies demand that the king renounce his wife Barbara Radziwiłł.
- December – Siam attacks Tavoy, beginning the Burmese–Siamese War of 1548.
- January – Burmese–Siamese War (1547–49): King Tabinshwehti of Burma begins his invasion of the Ayutthaya Kingdom, which ends in retreat.
- February 3 – Burmese–Siamese War: Burmese viceroy Thado Dhamma Yaza I of Prome slays Sri Suriyothai, queen consort of the Ayutthaya Kingdom, on her war elephant, when she intervenes in battle to protect the life of her husband.
- March 29 – The city of Salvador da Bahia, Brazil's first capital, is founded.
- June 9 – The Book of Common Prayer is introduced in English churches; the Prayer Book Rebellion against it breaks out in the West Country.
- July – Kett's Rebellion breaks out in East Anglia, against land enclosures; rebellion breaks out in Oxfordshire, against landowners associated with religious changes.
- July 27 – Francis Xavier arrives in Japan.
- August 8–9 – England and France declare war.
- August 17 – Battle of Sampford Courtenay in England: The Prayer Book Rebellion is quashed.
- August 26 – Battle of Dussindale in England: Kett's Rebellion is quashed.
- September 17 – The Council of Trent is prorogued indefinitely.
- November 4 – The Pragmatic Sanction is proclaimed by Charles V, Holy Roman Emperor. The Seventeen Provinces are declared inseparable.
- November 29 – The lengthy and large Papal conclave, 1549–50 goes into session in the Apostolic Palace in Rome, to decide on a successor to Pope Paul III.
- Peter Canisius starts the Counter-Reformation in Bavaria.
- The spire of Lincoln Cathedral in England is blown down, leaving St. Olaf's Church, Tallinn, in Estonia as the World's tallest structure.
- Although trade existed between the two beforehand, in this year the Portuguese begin to send regular seasonal maritime trade missions to Ming Dynasty China, at Sao João Island (also known as Shangchuan Island) near Macau.
- Excerpta antiqua is published by Hervagius at Basel, Switzerland.
- The Siege of Kajiki firearms are used for the first time in a siege in Japanese history. The Battle of Uedahara in the previous year was the first battle in which firearms are used.
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