Depp rose to prominence in a lead role on the television series 21 Jump Street and quickly became regarded as a teen idol. Uncomfortable with this career direction, he turned his focus to film roles. He initially came to film prominence as the titular character of Edward Scissorhands, and later found box office success in roles such as Ichabod Crane in Sleepy Hollow, Jack Sparrow in the Pirates of the Caribbean film series and Willy Wonka in Charlie and the Chocolate Factory.

He has collaborated with director and close friend Tim Burton in seven films, the most recent of which are Alice in Wonderland and Sweeney Todd: The Demon Barber of Fleet Street (2007). Depp has garnered acclaim for his portrayals of real life figures such as Edward D. Wood, Jr., in Ed Wood, Joseph D. Pistone in Donnie Brasco and George Jung in Blow (2001). More recently, he portrayed legendary bank robber John Dillinger in Michael Mann's 2009 film Public Enemies.

Films featuring Depp have grossed over $2.6 billion at the United States box office and over $5.7 billion worldwide. Nominated for the Academy Award for Best Actor three times, Screen Actors Guild Awards four times and Golden Globe Awards eight times, Depp won the Best Actor Awards from the Golden Globes for his role in Sweeney Todd: The Demon Barber of Fleet Street and from the Screen Actors Guild for Pirates of the Caribbean: The Curse of the Black Pearl.

Depp was born in Owensboro, Kentucky, the son of Betty Sue Palmer (née Wells), a waitress, and John Christopher Depp, Sr., a civil engineer. He has one brother, Daniel, who is a novelist, and two sisters, Christie (now his personal manager) and Debbie. Depp has German, Cherokee (mostly from a great-grandmother), and Irish ancestry. According to biographies, the Depp family originated with a French Huguenot, Pierre Deppe or Dieppe, who settled in Virginia around 1700. Depp has stated he did not know the origin of his surname, and joked about the name translating to "idiot" in German. The family moved frequently during Depp's childhood, and he and his siblings lived in more than 20 different locations, settling in Miramar, Florida, in 1970. In 1978, Depp's parents divorced. He engaged in self-harm as a child, due to the stress of dealing with family problems and his own insecurity. He has seven or eight self-inflicted scars. In a 1993 interview, he explained his self-injury by saying, "My body is a journal in a way. It's like what sailors used to do, where every tattoo meant something, a specific time in your life when you make a mark on yourself, whether you do it yourself with a knife or with a professional tattoo artist".

Depp's mother bought her son a guitar when he was 12, and Depp began playing in various garage bands. His first band was in honor of his girlfriend, Meredith. A year after his parents' divorce, Depp dropped out of high school to become a rock musician. As he once explained on Inside the Actors Studio, he attempted to go back to school two weeks later, but the principal told him to follow his dream of being a musician. He played with The Kids, a band that enjoyed modest local success. The Kids set out together for Los Angeles in pursuit of a record deal, changing their name to Six Gun Method but the group split up before ever signing a record deal. Depp subsequently collaborated with the band Rock City Angels and co-wrote their song "Mary", which appeared on Rock City Angels' debut for Geffen Records titled Young Man's Blues.

On December 24, 1983, Depp married Lori Anne Allison, a makeup artist and sister of his band's bass player and singer. During Depp's marriage, his wife worked as a makeup artist while he worked a variety of odd jobs, including a telemarketer for ink pens. Later, his wife introduced him to actor Nicolas Cage, who advised Depp to pursue an acting career. In 1985, Depp and Allison divorced. After his marriage ended, Depp dated and was engaged to Sherilyn Fenn (whom he met on the set of the 1985 short film Dummies).

Depp starred in a lead role on the Fox TV television series, 21 Jump Street, which premiered in 1987. Depp accepted this role because he was not getting much work in the business and wanted to work with actor Frederic Forrest, who inspired him. Later in the season, Depp's long time friend Sal Jenco joined the cast as a semi-co-star as the janitor named Blowfish. The series' success turned Depp into a popular teen idol during the late 1980s. He found the teen-idol status irritating, noting that he felt "forced into the role of product" and that it was "a very uncomfortable situation and I didn't get a handle on it and it wasn't on my terms at all." Depp promised himself that after his contract on the series expired, he would only appear in films that he felt were right for him.

Depp's first major role was in the 1984 horror film A Nightmare on Elm Street, playing the heroine's boyfriend and one of Freddy Krueger's victims. In 1986, he also appeared in a secondary role as a Vietnamese-speaking private in Oliver Stone's Platoon. Depp abandoned his teen idol image in 1990 with the quirky title role in the Tim Burton film, Edward Scissorhands. The film's success began a long association with Burton. Depp, an avid fan and long-time friend of writer Hunter S. Thompson, played a version of Thompson (named Raoul Duke) in 1998's Fear and Loathing in Las Vegas, based on the writer's pseudobiographical novel of the same name. Depp also accompanied Thompson as his road manager on one of the author's last book tours. In 2006, Depp contributed a personal foreword to Gonzo: Photographs by Hunter S. Thompson, a posthumous visual biography of the writer's legacy published by ammobooks.com. A close friend of Thompson's, Depp paid for most of Thompson's memorial event, complete with fireworks and the shooting of Thompson's ashes by a cannon, in Aspen, Colorado, where Thompson lived.

Depp's film characters have been described by the press as "iconic loners," and Depp has noted that this period of his career was full of "studio defined failures" and films that were "box office poison," stating that he believes film studios never "understood" the films he appeared in and did not know how to market them properly. Depp has also said that he specifically chose to appear in films that he found personally interesting, rather than those he thought would succeed at the box office.

Depp's status as a major star was solidified with the success of the 2003 Walt Disney Pictures film Pirates of the Caribbean: The Curse of the Black Pearl, for which his lead performance as the suave pirate Captain Jack Sparrow was highly praised. The performance was initially received negatively by the studio bosses who saw the film, but the character became popular with the movie-going public. In 2006, Bill Nighy, Depp's co-star from the sequel, Pirates of the Caribbean: Dead Man's Chest, described the role as probably being "one of the most popular performances of recent times." According to a survey taken by Fandango, Depp was also considered to be one of the main reasons audiences wanted to see the movie. The film's director, Gore Verbinski, has said that Depp's character closely resembles Depp's own personality, although Depp himself said that he modelled the character after Rolling Stones guitarist Keith Richards, who played Depp's father in At World's End. Depp, who has noted that he was "surprised" and "touched" at the positive reception given to the film, was nominated for an Academy Award for Best Actor for the role. In 2004, he was again nominated for an Academy Award for Best Actor, this time for playing Scottish author J. M. Barrie in the film Finding Neverland. Depp next starred as Willy Wonka in the 2005 film Charlie and the Chocolate Factory, which was a major success at the box office.