Banderas began his acting career with a series of films by director Pedro Almodรณvar in the 1980s; he then appeared in several Hollywood films, such as Philadelphia (1993), Interview with the Vampire (1994), Desperado (1995), Assassins (1995), Evita (1996), and The Mask of Zorro (1998). He also appeared in the Spy Kids series and provided the voice of Puss in Boots in the Shrek franchise and its spin-off film Puss in Boots in 2011.

In 2003, Banderas made his US theatre debut as Guido Contini in Nine, for which he was nominated for a Tony Award and won a Drama Desk Award. He received Primetime Emmy Award nominations for his roles in the television film And Starring Pancho Villa as Himself (2004) and the second season of Genius (2018); his portrayal of Pablo Picasso in the latter garnered him critical praise.

For the 2019 film Pain and Glory, Banderas earned the Cannes Film Festival Award, European Film Award and Goya Award for Best Actor, and received nominations for the Academy Award and Golden Globe Award for Best Actor.