Frank Harris was born James Thomas Harris in Galway, Ireland, February 14, 1856 of Welsh parents. At the age of 12 he was sent to Wales to continue his education as a boarder at the Ruabon Grammar School in Denbighshire, a time he was to remember later in My Life and Loves. Harris was unhappy at the school and ran away within a year.

Emigrating to the US in late 1869, he studied at the University of Kansas. In 1878 he married Florence Ruth Adams, who died the following year. Returning to England in 1882, Harris first came to general notice as the editor of a series of London papers including the Evening News, the Fortnightly Review and the Saturday Review, the last-named being the high point of his journalistic career, with H. G. Wells and George Bernard Shaw as regular contributors.

Harris returned to New York during World War I. From 1916 to 1922 he edited the U.S. edition of Pearson's Magazine. Pearson's has been described as "Probably second in fame to The Strand Magazine, which it imitated ... a heavily romantic publication".

Harris became an American citizen in April, 1921. In 1922 he traveled to Berlin to publish his best-known work, his autobiography My Life and Loves (published in four volumes, 1922—1927). It is notorious for its graphic descriptions of Harris's purported sexual encounters and for its exaggeration of the scope of his adventures and his role in history. A fifth volume, supposedly taken from his notes but of doubtful provenance, was published in 1954, long after his death.

Harris also wrote short stories and novels, two books on Shakespeare, a series of biographical sketches in five volumes under the title Contemporary Portraits and biographies of his friends Oscar Wilde and George Bernard Shaw. His attempts at playwriting were less successful: only Mr. and Mrs. Daventry (1900) (which was based on an idea by Oscar Wilde) was produced on the stage.

The "Frank Harris Publishing Company" was founded in New York in the mid-to-late 1920s to promote and distribute his works in America. Esar Levine, whose Harris collection is housed at Princeton University, was one of his employees and disciples. Married three times, Harris died in France on August 27, 1931, of a heart attack.

Harris appeared as a character in the play Oscar Wilde, written by Leslie & Sewell Stokes, at the Fulton Theatre, New York, 1938, starring Robert Morley in the title role.

Cowboy (1958) is an adaptation of the semi-autobiographical novel My Reminiscences as a Cowboy. Harris is played by Jack Lemmon.

He is seen as a minor character in The Trials of Oscar Wilde (1960) played by Paul Rogers.

On television, Harris was played by Leonard Rossiter in a 1978 BBC Play of the Week: Fearless Frank, or, Tidbits From The Life Of An Adventurer.

Harris was also featured in an episode of The Edwardians (1972) played by John Bennett.

He is a character in the 1997 Tom Stoppard play The Invention of Love, which deals with the life of A. E. Housman and the Oscar Wilde trials.

He appears as a close friend of Oscar Wilde in the award-winning play by Moisés Kaufman: The Three Trials of Oscar Wilde.

He appears in the first episode of the 2001 miniseries The Infinite Worlds of H. G. Wells, rejecting a story from Wells for being too long and too preposterous.

Harris appears as a vampire in Kim Newman's 1992 novel Anno Dracula, as the mentor and vampire sire of one of the novel's main characters.