Lilly was born in Geneva, New York on October 28, 1815. He moved to Lambertville, New Jersey in 1829, and attended Rev. P.O. Studdiford's classical school. He graduated from the University of Pennsylvania School of Medicine on March 31, 1837, and commenced practice in Lambertville.

He was elected as the first Mayor of Lambertville, New Jersey serving in office from 1849 to 1852.

Lilly was elected as a Democrat to the Thirty-third Congress, serving in office from March 4, 1853, to March 3, 1855. In Congress, he was chairman of the Committee on Expenditures in the Post Office Department.

He served as director of the Board of Chosen Freeholders of Hunterdon County for eight years, and was brigadier general of the New Jersey Militia. He was appointed by President James Buchanan as consul general of the United States to British India, with residence in Calcutta, from January 3, 1861, and served until July 4, 1862, when he resigned.

He was judge of the Court of Common Pleas of Hunterdon County from 1868–1873, and was one of the members of the board of managers of the New Jersey Insane Asylum in 1871. He was a judge of the New Jersey Court of Errors and Appeals, then the state's highest court, and also a member of the State board of pardons from 1873 until his death in Lambertville on April 3, 1880.

He died in 1880 and was interred in Mount Hope Cemetery in Lambertville.

• United States Congress. "Samuel Lilly (id: L000310)". Biographical Directory of the United States Congress.
• Samuel Lilly at The Political Graveyard
• Samuel Lilly at Find a Grave