At age 16 Depp dropped out of high school to pursue a music career. His band, the Kids, relocated from Florida, where he spent the majority of his childhood, to Los Angeles. In 1983 Depp married Lori Anne Allison, who worked as a makeup artist while he struggled as a musician. Allison had her friend and actor Nicolas Cage arrange for Depp to audition with director Wes Craven, and Depp made his film debut as a teenager eaten by his own bed in A Nightmare on Elm Street (1984). He divorced Allison the following year.

Depp's professional break came in 1987 with the premiere of 21 Jump Street, a television police series that starred Depp as Officer Tom Hanson, a young cop who frequently went undercover in high schools and colleges to catch troubled youths. The show was a hit, though Depp resented his promotion as a teen heartthrob. In 1990 he left the series and appeared in John Waters's Cry-Baby and Tim Burton's Edward Scissorhands, two films by maverick directors that showcased Depp's range. Scissorhands began a long association between the actor and director that led to Depp's appearance in several other Burton films, including Ed Wood (1994), Sleepy Hollow (1999), and Charlie and the Chocolate Factory (2005), in which Depp played the reclusive candy baron Willy Wonka. In addition, Depp provided the voice of the unfortunate groom in Burton's macabre animated tale Corpse Bride (2005).

Depp continued to show his versatility, appearing as a 19th-century accountant in Jim Jarmusch's Dead Man (1995) and as an FBI agent who infiltrates the Mafia in Donnie Brasco (1997). In 1998 Depp, a longtime friend and fan of gonzo journalist Hunter S. Thompson (Thompson, Hunter S.), starred in Terry Gilliam's Fear and Loathing in Las Vegas, a film based on Thompson's pseudobiographical novel of the same name. Later films include Roman Polanski's The Ninth Gate (1999) and Ted Demme's Blow (2001); while working on the former film, he met French actress and singer Vanessa Paradis, who became his partner.

Maintaining his early interest in music, Depp played acoustic guitar in the film Chocolat (2000) and on the sound track to Once Upon a Time in Mexico (2003). His work, as a guitarist, also appears on albums by the Pogues and Oasis.