Pitt was born in Shawnee, Oklahoma, the son of Jane Etta (née Hillhouse), a high school counselor, and William Alvin Pitt, a truck company owner. Along with his brother Doug and sister Julie Neal, he grew up in Springfield, Missouri, where the family moved soon after his birth. Pitt was raised a Baptist. He attended Kickapoo High School, where he was involved in sports, debating, student government, and acting. He attended the Missouri School of Journalism at the University of Missouri–Columbia. He is a member of the Sigma Chi Fraternity.

In 1988, Pitt had his first starring role, in The Dark Side of the Sun, where he played a young American taken by his family to the Adriatic to find a remedy for a skin condition. The movie was shot in Yugoslavia in the summer of 1988. However, with editing nearly complete, war broke out and much of the footage was lost; the film was released years later. Pitt was then cast in the television movie Too Young to Die?, about an abused teenager given the death penalty for murder. Pitt played the part of a drug addict, Billy Canton, who took advantage of a runaway played by Juliette Lewis.

In 1991, Pitt starred, along with Vera Martins, as Joe Maloney in Across the Tracks, in which he portrayed a high school runner with a difficult criminal brother played by Ricky Schroder. Pitt attracted broader public attention from a supporting role in Thelma & Louise, where he played a small-time criminal drifter who befriends Thelma (Geena Davis). His love scene with Davis, which showed Pitt topless and wearing a cowboy hat, has been referred to as "iconic", often cited as the moment that defined Pitt as a "sex symbol". After Thelma & Louise, Pitt starred alongside Catherine Keener and Nick Cave in the low budget, Tom DiCillo-directed 1991 film Johnny Suede, as an awkward dreamer who aspired to be a big-haired rock star. After appearing in Cool World, Pitt starred in Robert Redford's A River Runs Through It in 1992, for which Pitt learned fly fishing by casting off of Hollywood buildings. In 1993 came Kalifornia, a road movie in which he played a scruffy serial killer alongside Juliette Lewis and X-Files actor David Duchovny.

In 1994, Pitt played vampire Louis de Pointe du Lac in the movie adaptation of Anne Rice's novel Interview with the Vampire. The role of the eighteenth-century vampire required Pitt to endure several hours of make-up being applied every day to achieve the characteristic white skin; Pitt wore a pair of green contact lenses and vampire fangs to complete the appearance. Pitt's co-stars included the eleven-year-old Kirsten Dunst, Tom Cruise, Christian Slater, and Antonio Banderas. He then starred in Legends of the Fall and Se7en. In Se7en, Pitt starred alongside Morgan Freeman as the police detective David Mills who hunts a serial killer played by Kevin Spacey. Pitt was then nominated for an Academy Award as Best Supporting Actor for his portrayal of Jeffrey Goines in the 1995 film Twelve Monkeys.

In 1997, Pitt starred alongside Harrison Ford as the IRA terrorist Rory Devany in The Devil's Own, the first of several films where Pitt used an Irish accent in his performance. That same year he played the main role of Austrian mountaineer Heinrich Harrer in the Jean Jacques Annaud film Seven Years in Tibet. Pitt trained for months for the role, which demanded a great deal of trekking and mountain climbing, by rock climbing in California and the Alps with his co-star, David Thewlis. Due to the themes of Tibetan nationalism in the film, the Chinese government banned Pitt and Thewlis from entering China for life. In 1998, Pitt starred as the main character in the film Meet Joe Black, where he played a personification of Death inhabiting the body of a young man in order to learn what it is like to be human. The film gave Pitt another chance to work alongside Welsh actor Sir Anthony Hopkins, with whom he had previously worked on Legends of the Fall. In 1999, Pitt starred in Fight Club, an adaptation of Chuck Palahniuk's novel. Directed by Se7en's David Fincher, Pitt portrayed the highly complex and colorful character of Tyler Durden. In 2000, Pitt played the role of Mickey, an Irish Gypsy boxer in the gangster movie Snatch, alongside Jason Statham, Vinnie Jones and Benicio del Toro. The film was a wild caper involving a diamond heist, the Russian and American mafia and the shady underground world, that saw Pitt brought in as a ringer by two failing promoters. The movie saw him moving on from the Northern Irish accent he attempted in The Devil's Own; Pitt created a just-barely-intelligible accent suggesting the Irish Gypsies, referred to as Pikeys in the movie. Pitt continued to train for the role, and honed his boxing skills at Ricky English's gym in Watford.

In 2000, Pitt filmed the Cold War thriller Spy Game in which he starred alongside veteran actor Robert Redford, who played the role of his mentor. In 2001, Pitt worked with long-time friend Julia Roberts in the comical road movie The Mexican. At the end of the year, Pitt finished filming Ocean's Eleven with George Clooney and Matt Damon, a remake of the 1960s version which starred Frank Sinatra.

Since then, he has starred in numerous films, including Ocean's Twelve and the epic Troy, based on the Iliad, in which he portrayed the legendary hero Achilles. During film production of Troy, Pitt injured his Achilles tendon, delaying production for several weeks. In 2005, Pitt starred in Mr. & Mrs. Smith, in which he and Angelina Jolie played husband and wife assassins. In March 2006, it was announced that Paramount had purchased the rights to The Sparrow for Pitt's production company, Plan B, and that Pitt would be playing the lead role of Sandoz. In June 2006 it was announced that Paramount and Plan B will be working on a new zombie film called World War Z, based on the book of the same name by Max Brooks. Pitt made his return to Hollywood in late 2006 with Alejandro González Iñárritu's critically acclaimed Babel, starring alongside Cate Blanchett. The movie garnered a total of seven Academy Award and Golden Globe nominations, one of which was a Golden Globe nomination for Pitt as Best Supporting Actor in a Motion Picture. That same year, he also produced the eventual Best Picture winner, The Departed. In 2005, he produced and starred in The Assassination of Jesse James by the Coward Robert Ford, directed by Andrew Dominik, but the film was not released until late 2007.

Pitt has appeared in television commercials designed for the Asian market, advertising such products as Edwin Jeans. He also appeared in a Heineken commercial which aired during the 2005 Super Bowl; it was directed by David Fincher, who directed Pitt in the feature films Se7en and Fight Club. Together with Jennifer Aniston and Paramount Pictures head Brad Grey, Pitt founded the production company Plan B. Aniston is no longer a partner in the company, although she is still attached to many projects that were set up before her divorce from Pitt. The company produced the blockbuster Charlie and the Chocolate Factory, starring Johnny Depp, as well as The Departed and The Assassination of Jesse James by the Coward Robert Ford.

Pitt made a guest appearance in an eighth-season episode of Friends, as a man who has a grudge against Aniston's character Rachel Green, lent his voice on an episode of King of the Hill, where he played Boomhauer's brother, Patch Boomhauer, and appeared on an episode of MTV's Jackass, in which he took part in a staged abduction of himself. In a later Jackass episode, he and several cast members ran wild through the streets of Los Angeles in gorilla suits. Pitt has been an active supporter of research into diseases such as AIDS. He is the narrator of the acclaimed Public Television series Rx for Survival: A Global Health Challenge, which discusses current important global health issues. Pitt is behind Not On Our Watch, an organization that focuses global attention and resources to stop and prevent mass atrocities such as in Darfur, along with George Clooney, Matt Damon, Don Cheadle, and Jerry Weintraub. Pitt is also a knowledgeable fan of architecture, particularly that of Frank Lloyd Wright, and has helped the National Trust for Historic Preservation raise money.

In the late 1980s and 1990s, Pitt dated several of his co-stars, including Robin Givens (Head Of The Class), Jill Schoelen (Cutting Class), Juliette Lewis (Too Young to Die? and Kalifornia), who at sixteen was ten years his junior when they started dating, and Gwyneth Paltrow (Se7en), with whom he had a much-publicized engagement. Pitt also dated actresses Sinitta and Thandie Newton.