Depp's mother bought him a guitar when he was twelve, and he began playing in garage bands. His first band was in honor of his girlfriend Meredith. His parents divorced in 1978, and he dropped out of high school a year later to become a rock musician. (As he explained once on Inside the Actors Studio, he attempted to go back two weeks later, but the principal told him to follow his dream of being a musician, which Depp said was "really sweet.") He played with a band named "The Kids" which enjoyed modest local success. The band members set out together for Los Angeles in pursuit of a record deal, changing their name to "Six Gun Method." Depp's marriage caused friction between the band members, and the group split before signing a record deal. Depp subsequently collaborated with the band Rock City Angels and co-wrote the song "Mary", which appeared on their debut for Geffen Records, "Young Man's Blues".

He is a fan of The Rolling Stones and the gypsy musical group Taraf de Haidouks with whom he is friends. Another friend is singer, songwriter, and guitarist John Frusciante, whom Depp encouraged to record his first solo album after leaving the Red Hot Chili Peppers. He produced a mini-documentary called Stuff about John's life. He is friends with Marilyn Manson. Known to be a fan of the band Deadsy, Depp can be seen wearing a wristband with the band's logo in a segment on the Fear and Loathing DVD. He played slide guitar on the Oasis song "Fade In-Out" (from Be Here Now, 1997), as well on "Fade Away (Warchild Version)" (b-side of the "Don't Go Away" single). He played acoustic guitar in the movie Chocolat and on the soundtrack to Once Upon a Time in Mexico (he wrote "Sands' Theme", although the track is credited to "Tonto's Giant Nuts"). He performed on his long time friend Shane MacGowan's (Of The Pogues) first solo album and was a member of P, a group featuring Butthole Surfers singer Gibby Haynes. Additionally, he has appeared in the music videos of several artists, notably for Tom Petty & The Heartbreakers ("Into the Great Wide Open").

Soundtrack

• Sweeney Todd: The Demon Barber of Fleet Street (2007) (performer: "No Place Like London", "My Friends", "Pirelli's Miracle Elixir", "Pretty Women", "Epiphany", "A Little Priest", "Johanna (reprise)", "God, That's Good!", "By the Sea", "Final Sequence")
• Once Upon a Time in Mexico (2003) (writer: "Sands Theme") (producer: "Sands Theme")
• Chocolat (2000) ("Minor Swing/They're Red Hot/Caravan")