Colfax was the posthumous son of a bank clerk, Schuyler Colfax, and Hannah Stryker. After moving with his mother to Indiana in his youth, Colfax founded the St. Joseph Valley Register (1845), which became one of the most influential papers in the state during his 18 years as editor. In the fluctuating political situation preceding the American Civil War (1861–65), he shifted from the Whig Party to the Know-Nothing party and finally to the Republicans (Republican Party), who elected him to Congress in 1854. He served until 1869, the last six years as speaker of the House of Representatives (Representatives, House of).

During Reconstruction (1865–77), Colfax was a leader of the Radical Republicans (Radical Republican) and favoured extending suffrage to freedmen and disenfranchising former prominent officials of the Confederate States of America. Elected as Grant's vice president, he failed to win renomination in 1872. Later that year a congressional investigation implicated him—along with other politicians—in the Crédit Mobilier Scandal, which involved illegal manipulation of construction contracts for the building of the Union Pacific Railroad (Union Pacific Railroad Company). It was also revealed that in 1868 he had accepted a $4,000 campaign contribution from a contractor who had supplied the government with envelopes while Colfax was chairman of the Committee on Post Offices and Post Roads in Congress.

At the end of his term, Colfax returned to private life under a cloud but managed to make a living by delivering popular lectures.