Renfro was born in Knoxville, Tennessee. He was the son of Angela Denise Olsen (née McCrory) 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.  When he was ten, Renfro was discovered by Mali Finn, a casting director for Joel Schumacher. Cast by Finn as the lead in Schumacher’s The Client, Renfro starred alongside Susan Sarandon and Tommy Lee Jones. His casting was announced in May 1993, and the movie was filmed in the summer of that year. 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 1995, Renfro was cast in Sleepers, based on the novel by Lorenzo Carcaterra. The film was directed by Barry Levinson and co-starred Robert De Niro, Kevin Bacon, Dustin Hoffman, Ron Eldard and Brad Pitt.

In 1998, he starred opposite Ian McKellen in Apt Pupil, directed by Bryan Singer. The several films that followed gained little attention, the majority going straight to video. 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, and 2005’s The Jacket. He also appeared in an episode of Law & Order: Criminal Intent, and completed filming on the film The Informers, co-starring Mickey Rourke, Winona Ryder and Billy Bob Thornton.  Renfro was the cousin of Jesse Hasek, lead singer of the band 10 Years, and featured in the first version of the music video for their song “Wasteland”. He also featured in the video for N*E*R*D song Provider, playing the part of a petty drug dealer.  Renfro fathered one child: a son, Yamato Renfro, who was born in 2003. His name and age were initially withheld in Renfro’s obituary, which listed him as “Y. Renfro,” out of his family’s concerns for privacy. The existence of Yamato was not known to the general public until after his father’s death. He was raised solely in Japan by his mother.  Renfro recorded an album under the name Frodad Band which performed all over L.A. and made appearances at Sundance Film Festival.

Renfro was found dead on January 15, 2008 in his Los Angeles apartment. He was 25 years old. 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 Tennessee, where he was buried on January 22, 2008 north of Knoxville, at Red House Cemetery in the small community of Blaine.  Seventeen days after Renfro’s death, his grandmother Joanne—who had accompanied him regularly during his early acting career—died at her home at the age of 76.[20] Local officials stated that she died of natural causes.  Mark Foster of Foster the People was Renfro’s roommate and wrote a song about his death called “Downtown.”  In 2012, actor James Franco had the word “Brad” carved in his right arm in memory of Renfro, the documentation of which was included along with a small mirror emblazoned with the text “Brad Forever” as the 14th Edition of the art periodical, The Thing Quarterly. Franco also produced a limited edition series of switchblades bearing the words “Renfro” and “Forever.”