Brian Littrell was born in Lexington, Kentucky to Jackie and Harold Littrell. At five, he took a tumble from his Big Wheel tricycle that his doctors later assumed signified the start of a bacterial infection that began circulating in his blood. Nevertheless, Brian seemed perfectly fit. A few weeks later at his grandparents' house, Brian was messing around with his older brother when he slipped and fell, sustaining a nasty bump to his head. Worried that he might have a concussion, his mother took him to the hospital where the doctors discovered Brian's affliction. Brian was admitted immediately and started on a course of medication that the doctors doubted would cure him. The infection had gone too far, they said. The doctors actually told Brian's parents to prepare themselves for the worst. But faith sustained his family as Brian remained in hospital for two months gradually recovering. Not only was it the loneliest time of his life, but he admits that he sometimes still has nightmares about it. The doctors called Brian's recovery nothing short of a miracle.

He began singing as a child in his Baptist church and attended Tates Creek High School in Lexington. Littrell's cousin, Kevin Richardson moved to Orlando, Florida, during Littrell's teenage years. Richardson had gone to Orlando to find a job in the entertainment industry. After being chosen as one of the Backstreet Boys Richardson recommended his cousin to the band members and management. Even though Littrell was planning on attending Cincinnati Bible College and studying to become a youth pastor, he was convinced by Richardson to go to Florida and audition. Eventually, he was chosen as the fifth member of the band. Right from the start, when he was 18, he was one of the band's lead singers along with Nick Carterand AJ McLean and has solo parts in most of their singles. Besides being a pop singer, Brian explored other musical skills, such as playing the guitar and songwriting, co-writing some of the group's numbers (including 'Larger Than Life', 'The One' and 'The Perfect Fan').

The Backstreet Boysbegan to gain fame in 1995; by 1998, the group had fans of all ages all around the world. However, Littrell was soon faced with a serious problem because of his congenital heart problem, which nearly took his life at age four, had caused his heart to grow dangerously large. He was sent in and out of hospital through childhood. Doctors decided in May of that year to correct his problem by performing open heart surgery. His heart was enlarging due to the hole. Littrell was forced to cancel some concert tour dates as the doctors had warned him that if he kept on delaying the surgery, he would slowly kill himself.

After their success of the late 1990s, the Backstreet Boyswent on a hiatus. Littrell, meanwhile, became committed to a number of other show business activities, most of them for charity. The Backstreet Boysreunited in 2004 to start recording their new album, Never Gone. It was released in 2005, with their first single "Incomplete." The album "Never Gone" debuted at #1 in various countries and the single "Incomplete" became the Backstreet Boys first #1 in Australia's ARIA chart. "Never Gone" was quickly certified platinum in the US and selling over 3 million copies worldwide. The Backstreet Boys fifth album, Unbreakable, was released on October 29, 2007.

An outspoken Christian, Littrell has stated that he believes it is the duty of Christians to be open about their faith, saying, "I think as Christians we need to join hands and mount up together and lift God up and talk about our faith publicly and talk about all of the things God has done for us in our life to touch other people." Littrell, who has been a Born Again Christian since age 8, has said that he attributes his success in life to God, and that his faith has always been "the utmost important thing" in his life.

Littrell decided to make a Christian album and become a contemporary Christian singer, while maintaining his duties as the lead singer of the Backstreet Boys In the summer of 2005 Brian's solo single "In Christ Alone" went to #1 on the Christian Charts on July 4th and Littrell was the winner of the 2006 GMA Music Award for Inspirational Recorded Song of the Year, "In Christ Alone," which won both the 1993 award in this category and the 1994 Song of the Year at the GMA Music Awards. Brian's first solo album, Welcome Home (You) was released on May 2, 2006, which like the Backstreet Boysprojects, is a Sony BMG release. On May 10, 2007 he received an award from the Crystal Cathedral for being a positive role model using his music to touch lives in the pop and Christian market, and using his foundation to help children.