Littrell began singing as a child in church. His cousin, Kevin Richardson, moved to Orlando, Florida, during Littrell's teenage years. Kevin had gone to Orlando to find a job in the entertainment industry; after being chosen as one of the Backstreet Boys, he recommended his cousin Brian to the band members and management.

Brian was convinced by Kevin to go to Florida and audition. Soon, he was chosen as the fifth member of the band.

The Backstreet Boys began to gain fame in 1995; by 1998, the group had teenaged female fans around the world. However, Brian was soon faced with a serious problem because his congenital heart problem, which nearly took his life at age 5, had caused his heart to grow dangerously large. Doctors decided in September of that year to correct his problem by performing open heart surgery. Brian had to cancel some concert tour dates, but the surgery was successful, and his heart problem was corrected.

In 1997, Brian fell in love with model and actress Leighanne Wallace at the video shoot for their single "As Long As You Love Me." He proposed marriage in 1999 and the couple got married on September 2, 2000. They currently have one son, Baylee Thomas Wylee.

After their success of the late 1990s, the Backstreet Boys went on a hiatus. Brian, meanwhile, became committed to a number of other show business activities, most of them for charity. He joined other celebrities, such as Bow Wow, Frankie Muniz, Beyoncé Knowles, Usher Raymond, Jake Thomas and others, in a yearly NBA tour where he plays basketball in every NBA city before a game. Aside from that, he has also played charity baseball games and remains highly active in the charity he founded, the Brian Littrell Healthy Heart Club for Kids.

The Backtreet Boys reunited in 2004 to start recording their newest album, Never Gone. It was released in 2005, with their first single "Incomplete".

Brian's first solo album, "Welcome Home" is scheduled to be released May 2nd, 2006, and like the Backstreet Boys projects, is a Sony BMG release.