He was born on March 1, 1780, in Warwick, Rhode Island, he moved with his parents to Schenectady, New York, when he was a child. He received a liberal schooling and studied medicine, practicing in Trumansburg. He was a member of the New York State Assembly from 1810 to 1812 and was the first judge of New York Court of Common Pleas for Seneca County, holding that office from 1812 to 1815.

Comstock was elected as a Democratic-Republican to the Thirteenth, Fourteenth, and Fifteenth Congresses, holding office from March 4, 1813, to March 3, 1819. He was not a candidate for renomination in 1818, and was the first judge of court of common pleas for Tompkins County in 1817 and 1818. He abandoned the practice of medicine and studied theology. He was licensed to preach and ordained to the Baptist ministry; he was then installed as pastor of the First Baptist Church in Rochester and served in that capacity from 1825 to 1834. He was elected Chaplain of the House of Representatives on December 20, 1836, and served until March 3, 1837. He moved to Michigan and resumed ministerial duties at Detroit in 1839; from 1841 to 1843 he was a regent of the University of Michigan at Ann Arbor, and from 1843 to 1845 he was State superintendent of public instruction. Comstock died in Marshall, Calhoun County, Michigan, in 1860; interment was in Oakridge Cemetery.

• United States Congress. "Oliver C. Comstock (id: C000664)". Biographical Directory of the United States Congress.