Colfax's father contracted tuberculosis and died on October 30, 1822, five months before Colfax was born. His sister Mary died in July 1823, 4 months after he was born. His mother later remarried, becoming the wife of George W. Mathews. Colfax's mother and grandmother ran a boarding house as their primary means of economic support. Colfax attended private schools in New York City until he was 10, when family financial difficulties ended his formal education and caused him to take a job as a clerk in the store owned by his stepfather.

Schuyler Colfax was born on March 23, 1823, in New York City to Schuyler Colfax Sr. (born August 3, 1792), a bank Teller, and Hannah Delameter Stryker, who had married on April 25, 1820. His grandfather, william Colfax, served in George Washington's Life Guard during the American Revolution, became a general in the New Jersey militia and married Hester Schuyler, a cousin of General Philip Schuyler. william was commander at Sandy Hook during the War of 1812.

In 1836 Colfax's family moved to New Carlisle, Indiana. In 1841 Mathews was elected St. Joseph County Auditor, and he appointed Colfax as his deputy, a post which Colfax held for all eight years Mathews served as auditor.

On October 10, 1844, Colfax married childhood friend Evelyn Clark. She died childless in 1863. On November 18, 1868, two weeks after he was elected vice President, Colfax married Ellen (Ella) M. Wade (1836-1911), a niece of Senator Benjamin Wade. They had one son, Schuyler Colfax III (1870-1929), who served as mayor of South Bend, Indiana, from 1898 to 1901.

Colfax became interested in journalism and covered the Indiana Senate for the Indiana State Journal. In 1845 Colfax purchased the newspaper and changed its name to the St. Joseph Valley Register.

Colfax was a delegate to the 1848 Whig National Convention. He was also a delegate to the state constitutional convention of 1849-50. Colfax was the 1852 Whig nominee for Congress in the district which included South Bend, but narrowly lost to his Democratic opponent.

In addition to covering the Indiana Senate, Colfax contributed articles on Indiana politics to the New York Tribune, leading to a friendship with its Editor, Horace Greeley. At 19 Colfax became the Editor of the pro-Whig South Bend Free Press. He owned the Register for nine years, at first in support of the Whigs, then shifting to the Republican Party after its founding in the 1850s.

As a member of the Independent Order of Odd Fellows, Colfax, along with members william T. Martin of Mississippi and E. G. Steel of Tennessee, were appointed to prepare a Ritual of ceremonies pertaining to the Rebekah Degree and report at the 1851 session. On September 20, 1851, the IOOF approved the degree and Colfax was considered the author and founder.

In 1854 Colfax was initiated into the Beta Theta Pi fraternity at DePauw University, an achievement remarkable for the fact that he had not attended college.

In 1855 Colfax considered joining the Know Nothing Party because of the antislavery plank in its platform. He was selected, without his knowledge, to be a delegate to the party's June convention, but had mixed feelings about the party and subsequently denied having been a member. Although he agreed with many Know Nothing policies, he disapproved of its secrecy oath and citizenship test. By the time of his 1856 campaign for re-election, the Republican Party had formed as the main anti-slavery party, and Colfax became an early member.

Colfax was identified with the Radical Republicans in Congress, and was an energetic opponent of slavery. His speech attacking the pro-slavery Lecompton Legislature in Kansas was printed in pamphlet form, and became the most widely requested Republican campaign document in the 1858 mid-term elections.

After his arrival in St. Louis, Colfax met Frémont on September 14, 1861, and petitioned him to send troops to cut off Price from capturing Lexington. Colfax believed Frémont had 20,000 troops under his command in St. Louis. Frémont informed Colfax that he only had 8,000 troops in St. Louis and was unable to spare any. In addition Frémont told Colfax that Lincoln and federal authorities in Washington had requested him to dispatch 5,000 of his troops elsewhere. Colfax suggested that Frémont reply that he could not spare any troops or Missouri would be lost to the Confederacy. Frémont declined, recognizing that he had a reputation for being insubordinate, and not wanting to appear unwilling to follow the instructions of his superiors in the Lincoln administration. Frémont had earlier angered President Lincoln over his controversial August 30 edict that put Missouri under martial law and emancipated rebel slaves outside of the Confiscation Act. Price captured Lexington on September 20 and threatened to take the whole state of Missouri. Frémont finally responded on September 29. Having a force of thirty-eight thousand troops, he arrived at Sedalia southeast of Lexington, threatening to trap the rebels against the Missouri River. On September 29, Price abandoned Lexington, and soon was forced to abandon the state headed to Arkansas and later Mississippi.

In 1862, following Galusha A. Grow's defeat for reelection to his House seat, Colfax succeeded Grow as Speaker of the House.

In 1865, Colfax, along with author Samuel Bowles and Lieutenant Governor of Illinois william Bross, set out across the western territories from Mississippi to the California coast to record their experiences. They compiled their observations in an 1869 book called Our New West. Included in their book were details of the views of Los Angeles, with its wide panorama of vast citrus groves and orchards, and conversations with Brigham Young.

On September 17, 1867, Colfax addressed a Republican meeting in Lebanon, New York, on the political situation in Washington. Colfax said he was firmly against those who participated in the Confederate rebellion to be reinstated in office and control Republican Reconstruction policy. Colfax affirmed that he was not in any way for repudiating the debt caused by the Confederate rebellion. Colfax said Congressional reconstruction would give security and peace to the nation as opposed to President Johnson and his southern Democratic policies. Colfax favored Johnson's impeachment saying Johnson was recreant, an upsurper, and was unfaithful in executing the Reconstruction laws of the land in granting a general amnesty to all Southerners who participated in the Civil War. Colfax told Republicans who were tired of Reconstruction to leave the party and join the Democrats.

In addition to Colfax's involvement in the Crédit Mobilier scandal, the investigation revealed the more damaging accusation that Colfax had received a $4,000 gift also in 1868 from a contractor who supplied envelopes to the federal government while Colfax was chairman of the Committee on Post Offices and Post Roads, and so had influence in the awarding of such contracts.

Colfax was inaugurated March 4, 1869, and served until March 4, 1873. Grant and Colfax, 46 and 45 respectively at the time of their inauguration, were the youngest presidential and vice presidential team until the inauguration of Bill Clinton and Al Gore in 1993.

In September 1872, during the presidential campaign, Colfax's reputation was marred by a New York Sun article which indicated that he was involved in the Crédit Mobilier scandal. Colfax was one of several Representatives and Senators (mostly Republicans), who were offered (and possibly took) bribes of cash and discounted shares in the Union Pacific Railroad's Crédit Mobilier subsidiary in 1868 from Congressman Oakes Ames for votes favorable to the Union Pacific during the building of the First Transcontinental Railroad. Henry Wilson was among those accused, but after initially denying a connection, he provided a complicated explanation to a Senate investigating committee, which involved his wife having purchased shares with her own money, and then later canceling the transaction over concerns about its propriety. Wilson's reputation for integrity was somewhat dampened, but not enough to prevent him from becoming vice President.

Colfax's 20 years of public Service ended in controversy in 1873 due to the revelation that he was involved in the Crédit Mobilier scandal. He never returned to seek political office in part because he believed that it was best to stay out of politics once leaving office, and in part because he was content with his life as a private citizen. Because of his success as a lecturer, his reputation was somewhat restored. He had remained popular in his home area, and was often encouraged to run for office, including attempts to nominate him for his old U.S. House seat, but he always declined.

In 1875, he became vice President of the Indiana Reaper and Iron Company. On February 12, 1875, having returned to Washington, D.C., to give a lecture he advised his friends in Congress who were frustrated over the slow pace of action "Ah! the way to get out of politics is to get out of politics."

On April 3, 1882, Colfax announced in a letter to the South Bend Tribune that he declined to run for office again. Colfax said he appreciated that his friends had wanted him to become a candidate for his old U.S. House seat or another position, but that he was satisfied by the 20 years of Service he had given during the "stormiest years of our Nation's history." He also said that he was enjoying his life as a private citizen. Colfax said he would not accept any nomination even if tendered without his having campaigned, and that his "only ambition now is to go in and out among my townsmen as a private citizen during what years of life may remain for me to enjoy on this earth."

On January 13, 1885, Colfax walked about three-quarters of a mile (1 kilometer) in −30 °F (−34 °C) weather from the Front Street depot to the Omaha depot in Mankato, Minnesota, intending to change trains on his way to Rock Rapids, Iowa, to give a speech. Five minutes after arriving at the depot, Colfax died of a heart attack brought on by the extreme cold and exhaustion.

Actor Bill Raymond portrayed Colfax during his time as Speaker in the 2012 Steven Spielberg film Lincoln. The casting choice was interesting in that Raymond was in his early seventies when the film was made while Colfax was in his early forties when the movie was set, roughly the same as Speaker Paul Ryan who became speaker in 2015.