Jerome left school at the age of 14, working first as a railway clerk, then as a schoolteacher, an actor, and a journalist. His first book, On the Stage—and Off, was published in 1885, but it was with the publication of his next books, The Idle Thoughts of an Idle Fellow (1886) and Three Men in a Boat (1889), that he achieved great success; both books were widely translated. From 1892 to 1897 he was a coeditor (with Robert Barr and George Brown Burgin) of The Idler, a monthly magazine that he had helped found, which featured contributions by writers such as Eden Phillpotts, Mark Twain, and Bret Harte.

Jerome's many other works include Three Men on the Bummel (1900) and Paul Kelver (1902), an autobiographical novel. He also wrote a number of plays. A book of Jerome's memoirs, My Life and Times, was published in 1926.