
Cruz first achieved fame when she appeared in the video for "La fuerza del destino" for the Spanish synthpop group Mecano. She later started a relationship with Nacho Cano, a member of the group. A TV presenter for the teen-oriented program La Quinta Marcha, she also had early exposure in Série Rose, an erotic French TV serial. In one episode she played the role of a blind prostitute and in another played a young noblewoman pretending to be a young nobleman in a comedy of errors. She also directed Nacho Cano's video of "El waltz de los locos", in 1994.
Cruz's first major films were Jamón, jamón and Belle Époque, a film which won an Academy Award for Foreign Language Film. In 1997, she starred as Sofía Pangia, alongside Eduardo Noriega, in Open Your Eyes, directed by Alejandro Amenábar, while in 1999 she appeared in Pedro Almodóvar's All About My Mother, which also won an Academy Award for Foreign Language Film. In 2000 she appeared with Matt Damon in All the Pretty Horses.

In 2006, she co-starred with Salma Hayek in the film Bandidas. That same year, Cruz received highly favourable reviews for her performance in Pedro Almodóvar's Volver. She shared a Best Actress award at the Cannes Film Festival with five of her co-stars, and was nominated for the Golden Globe, the Screen Actors Guild Award, the BAFTA Award, and the Academy Award for Best Actress in a leading role. The latter of these nominations made her the first Spanish actress to be nominated for an Academy Award for Best Actress.

In 2008, Cruz appeared with Sir Ben Kingsley in fellow Spaniard Isabel Coixet's film Elegy, earning her critical praise for an English-speaking role. The film was based on the Philip Roth story The Dying Animal. She was nominated for a Golden Satellite award for her performance. Later that year, she starred in Woody Allen's Vicky Cristina Barcelona as María Elena, Javier Bardem's mentally unstable ex-wife.

Cruz again collaborated with Pedro Almodóvar in his film Los Abrazos Rotos, which is slated to be released in the U.S. in November 2009. She will also be featured in the film version of the musical Nine along with other Oscar winners Sophia Loren, Judi Dench, Daniel Day-Lewis, Nicole Kidman and Marion Cotillard.