George Samuel Schuyler was born in Providence, Rhode Island to George Francis (a chef) and Eliza Jane (Fischer) Schuyler. Schuler's paternal great-grandfather was believed to be a black soldier who worked for Philip Schuyler, whose surname the soldier adopted. Schuyler's maternal great-grandmother was a Malagasy servant who married a ship captain from Saxe-Coburg in Bavaria. Schuyler's father died when he was young. George spent his early years in Syracuse, New York, where his mother moved their family after she remarried. In 1912, Schuyler, at age seventeen, enlisted in the U.S. Army and was promoted to the rank of First Lieutenant, serving in Seattle and Hawaii. He went AWOL after a Greek immigrant, who was tasked to shine his shoes, refused to do so because of Schuyler's skin color. After turning himself in, Schuyler was convicted by a military court and sentenced to five years in prison. He was released after nine months as a model prisoner.

After his discharge, Schuyler moved to New York City, where he worked as a handyman, doing odd jobs. During this period, he read many books which sparked his interest in socialism. He lived for a period in the Phyllis Wheatley Hotel, run by black separatist Marcus Garvey's Universal Negro Improvement Association (UNIA) and attended UNIA meetings. Schuyler dissented from Garvey's philosophy and began writing about his perspectives.

Although not fully comfortable with socialist thought, Schuyler engaged himself in a circle of socialist friends, including the black socialist group Friends of Negro Freedom. This connection led to Schuyler's employment by A. Philip Randolph and Chandler Owen's magazine, The Messenger, the group's journal. Schuyler's column, Shafts and Darts: A Page of Calumny and Satire, came to the attention of Ira F. Lewis, manager of the Pittsburgh Courier. In 1924, Schuyler accepted an offer from the Courier to author a weekly column.

By the mid-1920s, Schuyler had come to disdain socialism. Schuyler believed that socialists were frauds who actually cared very little about negroes. Schuyler's writing caught the eye of journalist/social critic H. L. Mencken, who wrote "I am more and more convinced that he [Schuyler] is the most competent editorial writer now in practice in this great free republic." Schuyler was first published in the American Mercury, edited by Mencken, in December 1927. "[H]e became the most published Mercury writer, black or white, in Mencken's tenure as editor," wrote Mencken biographer Charles Scruggs. Because of his close association with Mencken as well as their compatible ideologies and sharp use of satire, during this period Schuyler was often referred to as "the Black Mencken."

In 1926, the Courier sent Schuyler on an editorial assignment to the South where he developed his journalist's routine: ride with a cab driver, then chat with a local barber, bellboy, landlord, and policeman. These encounters would precede interviews with local town officials. In 1926, Schuyler became the Chief Editorial Writer at the Courier. Also that year, he published an article entitled "The Negro-Art Hokum" in The Nation. Langston Hughes's "The Negro Artist and the Racial Mountain" appeared in the same magazine as a response to Schuyler's piece.

In 1929, Schuyler's pamphlet, Racial Inter-Marriage in the United States, called for solving the country's race problem through miscegenation, which was then illegal in most states.

In 1931, Schuyler published Black No More, which tells the story of a scientist who makes a machine that turns black people to white, a book that has since been reprinted twice. Between 1936 and 1938 in the Pittsburgh Courier he published a weekly serial, which he would later collect as a novel titled Black Empire. Schuyler also published the highly controversial book A Story of Liberia, a novel about the slave trade created by freed American slaves who settled Liberia in the 1920s.

Between 1933 and 1939, Schuyler published scores of short stories in the Pittsburgh Courier under various pseudonyms. Schuyler's articles also appeared in magazines, including The Nation, Negro Digest, American Mercury, and Common Ground.

From 1937 to 1944, Schuyler was the business manager of the NAACP. During the McCarthy Era, Schuyler moved sharply to the political right and contributed to American Opinion, the journal of the John Birch Society. In 1947, he published The Communist Conspiracy against the Negroes. In 1966, Schuyler was dismissed from the Pittsburgh Courier for his opposition to Martin Luther King Jr.'s being awarded the Nobel Peace Prize.

Schuyler’s conservatism was a counterpoint to the predominant liberal philosophy of the civil rights movement in the 1960s and 1970s. Outlets for Schuyler’s written work diminished until he was an obscure figure at the time of his death in 1977. As the liberal black writer Ishmael Reed notes in his introduction to a 1999 republication of Black No More, Schuyler's 1931 race satire, in the final years of Schuyler’s life it was considered taboo in black circles to even interview the aging writer.

He wrote a syndicated column (1965-77) for the North American Newspaper Alliance.

Schuyler's autobiography, Black and Conservative, was published in 1966.

In 1928, Schuyler married Josephine Lewis Cogdell, a liberal white Texan heiress. Their daughter, Philippa Schuyler (1931-1967), became a noted child prodigy and concert pianist.