In 1990, after numerous roles in teen-oriented films, his first of a handful of great collaborations with director Tim Burton came about when he portrayed the title role in Edward Scissorhands (1990). Following the film's success, Depp carved a niche for himself as a serious, somewhat dark, idiosyncratic performer, consistently selecting roles that surprised critics and audiences alike. He continued to gain critical acclaim and increasing popularity by appearing in many features before re-joining with Burton in the lead role of Ed Wood (1994). In 1997, he played the undercover FBI agent in the factually-based film Donnie Brasco (1997), opposite Al Pacino; in 1998, he appeared in Fear and Loathing in Las Vegas (1998), directed by Terry Gilliam; and then, in 1999, he appeared in the sci-fi/horror film The Astronaut's Wife (1999). The same year, he teamed up again with Burton in Sleepy Hollow (1999), brilliantly portraying Ichabod Crane.

Depp has played many characters in his career, including another factually-based character, Inspector Fred Abberline in From Hell (2001). He stole the show from screen greats such as Antonio Banderas in the finale to Robert Rodriguez's Mariachi trilogy, Once Upon a Time in Mexico (2003), in the same year as starring in the marvelous family blockbuster Pirates of the Caribbean: The Curse of the Black Pearl (2003), playing a character that only the likes of Depp could pull off, Captain Jack Sparrow. Now, Depp is collaborating again with Tim Burton in a new screen adaptation of Roald Dahl's novel, Charlie and the Chocolate Factory (2005).

Apart from his on-screen life, Depp has dated several female celebrities off-screen, including failed engagements to Jennifer Grey, Winona Ryder, and Kate Moss. He was married to Lori Anne Allison in 1983 but then divorced her in 1985. Currently, Depp is living with French singer-actress Vanessa Paradis, with whom he has two children: Lily-Rose Melody, born in 1999 and Jack, born in 2002.