Thompson frequently referred to himself as "Raoul Duke" or "Dr. Gonzo." He received his certification from a mail-order church in the sixties.

Thompson, originally a sports journalist writing for various publications, worked for Rolling Stone magazine during the late 1960s and 1970s and published several books and numerous articles. He is noted for the creation of gonzo journalism, a writing style that combines extravagance (including the use of diverse and sometimes multiple recreational drugs), and an eccentric personality.

Thompson's style of reportage meshes fact with drug-sotted fantasy; the archetypal example being Fear and Loathing in Las Vegas. Published in 1971, Fear and Loathing in Las Vegas is a travelogue of Thompson's trek (along with his attorney, Oscar Zeta Acosta) to cover a narcotics officers' convention in Nevada and the "fabulous Mint 400" motorcycle race. Instead, Thompson and Acosta wind up on a search for the American dream in Las Vegas with the aid of heroic amounts of LSD, ether, adrenochrome, and numerous other drugs.

Some of Thompson's other books include Fear and Loathing on the Campaign Trail '72, a collection of Rolling Stone articles he wrote while covering the campaigns of President Richard M. Nixon and his unsuccessful opponent, Senator George McGovern, and Hell's Angels, an account of his travels with the infamous motorcycle gang. His penultimate book, Kingdom of Fear, is an angry commentary on the passing of the American Century. Thompson also wrote a Web column, "Hey Rube," for ESPN. He has at times also toured on the lecture circuit, once with John Belushi.

Cartoonist Garry Trudeau based his Doonesbury character Uncle Duke on Thompson, to loud protests from Thompson himself. A slogan of Thompson's, "When the going gets weird, the weird turn pro", appears as a chapter heading in Fear and Loathing in Las Vegas. Another closely-related Gonzo journalist is Timothy Edward Jones, author of the highly-acclaimed book European Confession.

Thompson was an admitted fan of firearms and was known to keep a keg of gunpowder in his basement.