Depp was born in Owensboro, Kentucky, the youngest of four children of Betty Sue Palmer (née Wells), a waitress, and John Christopher Depp, a civil Engineer. Depp is of mostly English ancestry, with some ancestors from elsewhere in Europe. He is descended from a French Huguenot immigrant, Pierre Deppe or Dieppe, who settled in Virginia around 1700. He is also of 3/2048 African descent, as he descends twice over from an African slave whose biracial daughter, Elizabeth Key Grinstead, was the first woman of Sub-Saharan African ancestry in North America to sue for her freedom from slavery and win (in 1655).

Depp moved frequently during his childhood. He and his siblings lived in more than 20 different places, eventually settling in Miramar, Florida in 1970. Depp's parents divorced in 1978 when he was 15. His mother married Robert Palmer, whom Depp has called "an inspiration to me."

Depp became a popular teen idol during the late 1980s, when he starred as a police officer who goes on an undercover operation in a high school in the Fox television series 21 Jump Street, which premiered in 1987. He accepted this role to work with actor Frederic Forrest, who inspired him. Despite his success, Depp felt that the series "forced [him] into the role of product." He subsequently decided to appear only in films that he felt were right for him. Depp's first film release in 1990 was John Waters' Cry-Baby, a musical comedy set in the 1950s. Although it was not a box office success upon its initial release, over the years it has gained a cult classic status. Depp's second 1990 film was Tim Burton's film Edward Scissorhands, in which he played the title character opposite Dianne Wiest and Winona Ryder. It was a critical and commercial success that established him as a leading Hollywood actor and began his long association with Burton. Producer Scott Rudin has stated that "basically Johnny Depp is playing Tim Burton in all his movies"; although Burton disapproved of the comment, Depp agrees with it. In his introduction to Burton on Burton, a book of interviews with the Director, Depp called Burton "... a brother, a friend, ... and [a] brave soul".

Depp married makeup Artist Lori Anne Allison on December 20, 1983; they divorced in 1985. He was later engaged to actresses Jennifer Grey and Sherilyn Fenn in the late 1980s before proposing in 1990 to his Edward Scissorhands co-star Winona Ryder, for whom he tattooed "WINONA FOREVER" on his right arm. From 1994 until 1998, he was in a relationship with English supermodel Kate Moss.

Depp's first film role was in the horror film A Nightmare on Elm Street (1984), in which he played the boyfriend of heroine Nancy Thompson (Heather Langenkamp) and one of Freddy Krueger's victims. After a starring role in the comedy Private Resort (1985), Depp was cast in the lead role of the skating drama Thrashin' (1986) by the film's Director, but the decision was later overridden by its Producer. Instead, Depp appeared in a minor supporting role as a Vietnamese-speaking private in Oliver Stone's Vietnam War drama Platoon (1986).

Depp has taken on the task of challenging himself to portray "larger-than-life" roles, starting with a supporting role in Oliver Stone's Vietnam War film Platoon in 1986, then playing the title character in the romantic dark fantasy Edward Scissorhands (1990). He later found box office success in the fantasy adventure film Sleepy Hollow (1999), the fantasy swashbuckler film Pirates of the Caribbean: The Curse of the Black Pearl (2003) and its sequels, the fantasy film Charlie and the Chocolate Factory (2005), the fantasy film Alice in Wonderland (2010) and voicing the title character in the animated action comedy western Rango (2011). He has collaborated on nine films with Director, Producer and friend Tim Burton.

Depp was arrested in Vancouver in 1989 for assaulting a security guard after the police were called to end a loud party at his hotel room. He was also arrested in New York City in 1994 after causing significant damage to his room at the Mark hotel, where he was staying with Kate Moss. The charges were dropped against him after he agreed to pay $9,767 in damages. Depp was arrested again in 1999 for brawling with paparazzi outside a restaurant while dining in London with Paradis.

Depp had no film releases in the following two years, with the exception of a brief cameo in Freddy's Dead: The Final Nightmare (1991), the sixth installment in the A Nightmare of Elm Street franchise. He appeared in three films in 1993. In the romantic comedy Benny and Joon, he played an eccentric and illiterate silent film fan who befriends a mentally ill woman and her brother; it became a sleeper hit. He then starred alongside Leonardo DiCaprio and Juliette Lewis in Lasse Hallström's What's Eating Gilbert Grape, a drama about a dysfunctional family. In his review of the film, Todd McCarthy of Variety said that "Depp manages to command center screen with a greatly affable, appealing characterization." Depp's final 1993 release was Emir Kusturica's surrealist comedy-drama Arizona Dream, which opened to positive reviews.

In 1994, Depp reunited with Director Tim Burton, playing the title role in Ed Wood, a biographical film about one of history's most inept film Directors. Depp later stated that he was at the time depressed about films and filmmaking, but that "within 10 minutes of hearing about the project, I was committed." He found that the role gave him a "chance to stretch out and have some fun" and that working with Martin Landau, who played Bela Lugosi, "rejuvenated my love for acting". Ed Wood received critical acclaim, with Janet Maslin of The New York Times writing that Depp had "proved himself as an established, certified great actor" and "captured all the can-do optimism that kept Ed Wood going, thanks to an extremely funny ability to look at the silver Li Ning of any cloud." Depp was nominated for Golden Globe Award for Best Actor – Motion Picture Musical or Comedy for his performance.

Depp played slide guitar on the Oasis song "Fade In-Out" (from Be Here Now, 1997), as well as on "Fade Away (Warchild Version)" (B-side of the "Don't Go Away" single). He also played acoustic guitar in the film Chocolat and on the Soundtrack to Once Upon a Time in Mexico. "He's playing guitar around the fire," observed Depp's friend and Future Hollywood Vampires bandmate Joe Perry of Chocolat. "And that's really him playing the guitar. He was playing Django Reinhardt stuff that I didn't have a clue about… In some ways, he's a better guitar player than I am."

Following his breakup from Moss, Depp began a relationship with French actor and singer Vanessa Paradis, whom he met while filming The Ninth Gate in France in 1998. They have two children, daughter Lily-Rose Melody Depp (born 1999) and son John "Jack" Christopher Depp III (born 2002). Depp stated that having children has given him "real foundation, a real strong place to stand in life, in work, in everything ... You can't plan the kind of deep love that results in children. Fatherhood was not a conscious decision. It was part of the wonderful ride I was on. It was destiny. All the math finally worked." In 2007, Depp's daughter was hospitalized at the Great Ormond Street Hospital in London due to a serious E. coli infection, which resulted in temporary kidney failure. To show his gratitude for her recovery, Depp visited the hospital in November 2007, dressed in his Captain Jack Sparrow outfit, and spent four hours reading stories to the children. He also donated £1 million to the hospital the following year. Depp and Paradis announced their separation in June 2012.

Depp's next venture with Burton was the period film Sleepy Hollow (1999), in which he played Ichabod Crane opposite Christina Ricci and Christopher Walken. For his performance, Depp took inspiration from Angela Lansbury, Roddy McDowall and Basil Rathbone. He stated that he "always thought of Ichabod as a very delicate, fragile person who was maybe a little too in touch with his feminine side, like a frightened little girl."

In interviews in 2002 and 2011, Depp claimed he has Native American ancestry, and that “I was told I was Cherokee as a kid. I was told I was Creek Indian as a kid and Chickasaw.” He has also claimed that his "great-grandmother was quite a bit of Native American." He has no evidence for these claims, only personal belief and Kentucky lore among non-Natives. Depp's genealogy has since been done by third-party researchers, who discovered the ancestors he believed to be Native actually had very distant African-American ancestry. Despite this discovery, Depp has continued to claim or imply he is Native. Depp's claims came under question when Indian Country Today Media Network stated that Depp has never inquired about his heritage nor does the Cherokee Nation recognize him as a member. This has led to criticism from the Native community, including of his choice to portray Tonto, a Native American character, in The Lone Ranger. Critical response to his claims from the Native community also included satirical portrayals of Depp by Native comedians.

In 2003, Depp starred in the Walt Disney Pictures adventure film Pirates of the Caribbean: The Curse of the Black Pearl, which was a major box office success. He earned widespread acclaim for his comic performance as pirate Captain Jack Sparrow, and received a nomination for the Academy Award for Best Actor. Depp has said that Sparrow is "definitely a big part of me", and that he modeled the character after The Rolling Stones Guitarist Keith Richards and cartoon skunk Pepé Le Pew. Studio executives had at first been ambivalent about Depp's portrayal, but the character became popular with audiences. According to a survey taken by Fandango, Depp was a major draw for audiences.

In 2004, Depp formed his production company Infinitum Nihil to develop projects where he will serve as actor or Producer. Depp is the founder and CEO, while his sister, Christi Dembrowski, serves as President. The company's first production came in 2011 with The Rum Diary, adapted from the novel of the same name by Hunter S. Thompson. The film is written and directed by Bruce Robinson. Also in 2011, Hugo, directed by Martin Scorsese, was released. Dark Shadows, directed by Tim Burton, was released in 2012.

Depp stated to the German magazine Stern in 2003 that "America is dumb, is something like a dumb puppy that has big teeth—that can bite and hurt you, aggressive." Although he later asserted that the magazine misquoted him and his words were taken out of context, Stern stood by its story, as did CNN.com in its coverage of the interview. CNN added his remark that he would like his children "to see America as a toy, a broken toy. Investigate it a little, check it out, get this feeling and then get out." The July 17, 2006 edition of Newsweek reprinted the "dumb puppy" quotation, verbatim, in the context of a Letter to the Magazine. Depp has also disagreed with subsequent media reports that perceived him as a "European wannabe", saying that he liked the anonymity of living in France while in a relationship with Paradis and his simpler life there. Depp became a U.S. resident again in 2011, because France wanted him to become a permanent resident, which he said would require him to pay income tax in both countries.

In Director Terry Gilliam's 2009 film The Imaginarium of Doctor Parnassus, Depp, Jude Law, and Colin Farrell each played the character initially portrayed by their friend Heath Ledger, who died before the film was completed. All three actors gave their salaries to Ledger's daughter Matilda. The next Depp-Burton collaboration was Alice in Wonderland (2010), in which he played the Mad Hatter alongside Helena Bonham Carter, Anne Hathaway and Alan Rickman. The following year saw the release of the fourth installment in the Pirates series, On Stranger Tides (2011), which was again a box office success. Depp also voiced the title character, a lizard, in the animated film Rango (2011), and returned to Hunter S. Thompson's work with a film adaptation of the novel The Rum Diary, which also became the first project undertaken by his production company, Infinitum Nihil.

He has appeared in music videos for Tom Petty & The Heartbreakers' "Into the Great Wide Open", The Lemonheads' "It's a Shame About Ray", Avril Lavigne's "Alice" (as the Mad Hatter) in 2010, and "My Valentine" from Kisses on the Bottom by Paul McCartney released in February 2012, along with Natalie Portman.. He played lead guitar and drums on a cover of Carly Simon's "You're So Vain" – a bonus cut on Marilyn Manson's 2012 album Born Villain – and performed several songs with Manson at the Revolver Golden Gods Awards in 2012.

On the October 16, 2011 episode of Larry King Live, when asked if he had faith, Depp replied, "Yes. I have faith in my kids. And I have—I have faith, you know, that as long as you keep moving forward, just keep walking forward, things will be all right, I suppose, you know. Faith in terms of religion, I don't—religion is not my specialty, you know."

Depp was adopted as an honorary son by LaDonna Harris, a member of the Comanche Nation, on May 22, 2012, making him an honorary member of Harris's family but not a member of any tribe.

In 2012, disabled UC Irvine medical professor Robin Eckert sued Depp and three security firms, claiming to have been attacked by his Bodyguards at a concert in Los Angeles in 2011. During the incident, she was allegedly hand-cuffed and dragged 40 feet across the floor, resulting in injuries including a dislocated elbow. She argued in court that, as the security guards' direct manager, Depp failed to intervene, even though he did not actively take part in the battery. In October 2012, it was decided that Eckert could seek compensation and punitive damages from Depp, with a trial date set for August 12, 2013. Depp ultimately settled with Eckert for an undisclosed sum.

In April 2015, Heard and Depp breached Australia's strict biosecurity laws when they failed to declare their two Yorkshire Terriers to the Australian Customs Service when they flew by private jet into Queensland, where he was working on the fifth Pirates installment. Australian quarantine regulations, which are aimed at keeping rabies out of the country, require dogs from outside the country be quarantined a minimum of ten days. Heard was charged with two counts of illegally importing the dogs into the country and one count of producing a false document. Shortly afterward, Agriculture Minister Barnaby Joyce said, "If we start letting movie stars even though they've been the 'sexiest man alive' twice to come into our nation, then why don't we just break the laws for everybody? It's time that Pistol and Boo [the dogs] buggered off back to the United States." In September 2015, when promoting his film Black Mass at a press conference for its world premiere in Venice, Depp joked that he "killed his dogs and ate them ... under direct orders from some kind of sweaty big-gutted man from Australia."

In March 2016, Depp cut ties with his management company, the Management Group, and accused them of improperly managing his money. The Management Group later sued Depp for unpaid fees and countersued him for damages alleging that Depp was responsible for his own fiscal mismanagement. Depp filed new papers, including receipts from America's Internal Revenue Service (IRS), to have the countersuit dismissed.

By March 27, 2017, Depp was cast to portray antivirus software developer John McAfee in a forthcoming film titled King of the Jungle. Glenn Ficarra and John Requa will direct the film, while Scott Alexander and Larry Karaszewski will write the script.

Depp will return as Gellert Grindelwald in Fantastic Beasts: The Crimes of Grindelwald. Filming will start in August 2017, with locations in the UK and Paris. David Yates will be directing the movie from a script by J. K. Rowling. The film is a sequel of Fantastic Beasts and Where to Find Them. It is set for release in November 16, 2018.