Brad Renfro was born in Knoxville, Tennessee, the son of Angela and Mark Renfro, who was a factory worker. He was raised from the age of five by his paternal grandmother, Joanne Barron Renfro, a church secretary.

Renfro was discovered by Mali Finn, a casting director for Joel Schumacher, when he was 10. His only previous acting experience was as a dealer in an anti-drugs workshop school production. Cast by Finn for Schumacher's The Client, Renfro acted alongside Susan Sarandon and Tommy Lee Jones. Based on the bestselling John Grisham novel, it became one of the top-grossing films of 1994. In 1995, he won Hollywood Reporter's "Young Star" award, and was nominated as one of People's "Top 30 Under 30". That year, he played Huckleberry "Huck" Finn in 1995's Tom and Huck with Jonathan Taylor Thomas. He also won a second "Young Star" award, as well as the "Young Artist" award, for his performance in The Cure.

In 1996, he was cast in Sleepers, based on the novel by Lorenzo Carcaterra. The film was directed by Barry Levinson and also starred Robert De Niro, Kevin Bacon, Dustin Hoffman and Brad Pitt.

In 1998, he starred opposite Ian McKellen in Apt Pupil, directed by Bryan Singer. That same year, he played Leon S. Kennedy in a live-action preview of Resident Evil 2. Renfro went on to act in other films, including 2001's Ghost World and Bully, 2002's Confessions of an American Girl (in which he played a gay teenager), and 2005's The Jacket. He also appeared in an episode of Law & Order: Criminal Intent and completed filming on the unreleased film The Informers, co-starring Winona Ryder and Billy Bob Thornton.

Renfro was the cousin of Jesse Hasek, lead singer of the band 10 Years,[citation needed] and was featured in the first version of their video for the song "Wasteland". He fathered a son named Yamato Renfro, born in 2003. The boy lives in Japan with his mother.

In December 2005, he was arrested by LAPD officers during an undercover drug sweep of downtown's skid row and was charged with attempted possession of heroin. A photograph showing him in handcuffs made the front page of the Los Angeles Times. Renfro admitted to a detective that he was using heroin and methadone. In court, he pleaded guilty to the charges, and was sentenced to three years' probation. In 2006, he spent 10 days in jail for convictions of driving while under the influence and attempted heroin possession.

Renfro was found dead on January 15, 2008 in his Los Angeles apartment. On February 8, 2008, the Los Angeles County Coroner's office ruled that Renfro's death was accidental, attributing it to acute heroin/morphine intoxication. His body was returned to East Tennessee, where he was buried on January 22, 2008 north of Knoxville, at Red House Cemetery in the small community of Blaine.

Less than two weeks later, his grandmother Joanne – who had raised him and accompanied him regularly during his early acting career – died at her home at the age of 76. Local officials stated that she died of natural causes.