Santangelo reached the fourth round at the 2004 Australian Open, defeating 16th-seeded Magüi Serna, Barbara Schett, and 19th-seeded Eleni Daniilidou—losing to eventual champion and world No. 1 Justine Henin, after having been up 4–2 in the second set. She also won her first WTA Tour title in 2006, defeating Jelena Kostanić in the final.

She took a set from top-seeded Amélie Mauresmo in the third round of the 2006 US Open, and led 2–0 in the deciding set, only to lose the next six games. She also defeated Anastasia Myskina in 2006, her first win over a top-20 player. She and her Italian teammates Francesca Schiavone, Flavia Pennetta, and Roberta Vinci beat the Belgian team 3–2 in the 2006 Fed Cup final. Justine Henin had to retire in the fifth and final match because of an injury in her right knee, which let Italy win their first Fed Cup trophy.^[1]

Despite holding match points in both matches, Santangelo lost to Agnieszka Radwańska and Dinara Safina in successive first rounds at Luxembourg and Stuttgart respectively, in three set matches. In Moscow, Santangelo lost in the first round to Iveta Benešová in another three-setter. In Linz, Santangelo defeated Alona Bondarenko; she lost to eventual semifinalist Nicole Vaidišová. At her final tournament of the year in Hasselt, Santangelo retired while 5–2 down against Michaëlla Krajicek in the first round. She ended the year ranked world No. 31, a new career high.

Santangelo was still recovering from injury when 2007 commenced. At her first tournament in Hobart, she defeated countrywoman Maria Elena Camerin in the first round, losing to Catalina Castaño in the second round. At the Australian Open, Santangelo drew then-world No. 81 eventual champion Serena Williams in the first round, losing in two sets. She reached her first quarterfinal of the year at the Tier IV Pattaya City tournament, losing to Sania Mirza in straight sets. At her very next tournament, the Tier III Bangalore, as the defending champion, Santangelo made the final for the second straight year, where she lost to Yaroslava Shvedova in the final.

In Doha during the second round, Santangelo faced fellow countrywoman Francesca Schiavone, and led 6–4, 6–6 (6–5), but lost 6–4, 6–7, 0–1 retired after dropping a match point. She rebounded during her next tournament, however, in Key Biscayne, defeating Jelena Janković in the third round in three sets – which was the first top 10 victory of her career. She lost in the round of 16 to Anna Chakvetadze. Reaching the fourth round of Key Biscayne has thus far been the best showing of Santangelo's in a high-tier event.

During the clay court season, Santangelo defeated Nadia Petrova in the second round of Warsaw, for her second career top-10 victory, reaching her third quarterfinal of the year. She lost to eventual champion Henin. At the French Open, in singles, Santangelo reached the third round, losing to eventual champion Henin. For doubles, however, partnering Alicia Molik, she won the championship, winning her first Grand Slam title. The victory was her fourth title in doubles for the year, with four different partners at each championship.

In 2007 Wimbledon Championships, Santangelo was defeated in round three by the defending champion and fourth-seeded, Amélie Mauresmo, in 57 minutes. Santangelo took part in the 2007 Fed Cup final, where she was defeated by Svetlana Kuznetsova in the second rubber and by Elena Vesnina in the fourth rubber; Italy failed in defending the title and Russia won the trophy with a 4–0 score. Santangelo had to miss the warm-ups for the Australian Open and the Australian Open itself in 2008 because of a troublesome left foot injury. She also missed the Paris indoors event and the Bangalore Open event, where she had previously won a WTA-level title and been a runner-up.

Santangelo returned from eight-month left foot injury lay-off in May; she reached the second round twice (including the 2008 Wimbledon Championships) and she won two ITF tournaments, Biella and Ortisei. At the Beijing Olympics, she was defeated by Dinara Safina in the first round.

In 2009, once again plagued by her foot injury, Santangelo won three doubles tournaments, all of them partnering Nathalie Dechy: Auckland Open where they defeated Nuria Llagostera Vives and Arantxa Parra Santonja, the Monterrey Open with a two-sets win over Iveta Benešová and Barbora Záhlavová-Strýcová and, finally, Strasbourg, defeating Claire Feuerstein and Stéphanie Foretz with a 6–0, 6–1 score. On 6 September, partnering Laura Olivieri, she won the 2009 European Beach Tennis Championships with a straight-sets win over the defending champions, Simona Briganti and Rossella Stefanelli.^[2]

In May 2010, Santangelo announced her decision to compete in doubles events only, citing her recurrent left foot injury as the main cause that persuaded her to renounce to play singles matches.^[3] On 28 January 2011, she declared her retirement from professional tennis due to recurring injuries with her left foot.

Santangelo was born in Latina, but grew up in the Fiemme Valley in Trentino. She started playing tennis at the age of 6. Her mother, Patrizia, died in a car accident in 1997, when she was sixteen.

Santangelo is a Catholic.^[4] In 2010, she went on a pilgrimage to Our Lady of Medjugorje, and has been vocal about her faith since then. Santangelo has written an autobiography, Te lo prometto (I promise you), based on her tennis career and spiritual life.^[5]

Doubles: 1 (1–0) edit

Singles: 2 (1–1) edit

Doubles: 12 (9–3) edit

Singles (8–4) edit

Doubles (14–5) edit

Singles edit

Doubles edit

Players who have been ranked world No. 1 are in boldface.

• Mara Santangelo at the Women's Tennis Association  
• Mara Santangelo at the International Tennis Federation  
• Mara Santangelo at the Billie Jean King Cup  
• Mara Santangelo Official website