After beginning his career writing for the National Lampoon, O'Rourke went on to serve as foreign affairs desk chief for Rolling Stone where he reported from far-flung places.

The Forbes Media Guide Five Hundred, 1994 states, "O'Rourke's original reporting, irreverent humor, and crackerjack writing makes for delectable reading.

[6] Many of O'Rourke's essays recount that during his student days he was a leftist, anti-war hippie, but that in the 1970s his political views underwent a volte-face.

for The Rip Off Review of Western Culture, an underground magazine/comic book, in 1972, as well as pieces for the Baltimore underground newspaper Harry and the New York Ace, before joining National Lampoon in 1973, where he served as editor-in-chief, among other roles, and authored articles such as "Foreigners Around the World"[9] and "How to Drive Fast on Drugs While Getting Your Wing-Wang Squeezed and Not Spill Your Drink".

[10] O'Rourke received a writing credit for National Lampoon's Lemmings which helped launch the careers of Chevy Chase and Christopher Guest.

[15] During the Bosnian genocide, O'Rourke referred to the American public's lack of interest in Bosnia as a way to joke about "the unspellables killing the unpronounceables".

[21][24] O'Rourke was a proponent of gonzo journalism; one of his earliest and best-regarded pieces was "How to Drive Fast on Drugs While Getting Your Wing-Wang Squeezed and Not Spill Your Drink", a National Lampoon article in March 1979.

[27] O'Rourke's best-received book is Parliament of Whores, subtitled A Lone Humorist Attempts to Explain the Entire U.S. Government, whose main argument, according to the author, "is that politics are boring".

[29] O'Rourke typed his manuscripts on an IBM Selectric typewriter, though he denied being a Luddite, asserting that his short attention span would have made focusing on writing on a computer difficult.