His comedy material is mostly observational humor. His recent routines include such diverse topics as car accident mayhem, Cook often refers to specific places or things using his own slang terms. For instance: Burger King is the "BK Lounge", Walgreens is "The Wall", and a sandwich is a "sangwich". Among Cook's numerous television credits are performances on Comedy Central Presents.

When he was a teenager, Dane Cook discovered his comedic talent when his father, former radio personality George Cook, gave him a tape recorder and microphone. He was inspired by watching and listening to a variety of comedians, including Bill Cosby, Johnny Carson, George Carlin and even Red Skelton.

He started performing stand-up comedy in 1990. By 1995, Cook was performing stand-up comedy every night, usually in Boston and, when he made it to Los Angeles, at The Laugh Factory. He stated in a 2005 interview with Entertainment Weekly that he "never walked toward a stage and felt heavy, Ever. Even in bad places, I always learned something."

In 1999, he made his first appearance in a major motion picture as "The Waffler"  in Mystery Men. A year earlier, he was featured on Comedy Central's stand-up comedy showcase Premium Blend and, the following year, Comics Come Home.

In 2003, Cook released his first comedy album, Harmful If Swallowed, which also included a DVD of his appearances on Comedy Central.