Brain McKnight was born in Buffalo, New York. His musical career began in childhood when he became a member of his church choir and a band leader for his high school, Sweet Home High School.
In 1997, McKnight recorded "Remember the Magic" for Disney World's 25th anniversary.
In October 2007, McKnight made his Broadway debut in the show Chicago.
From 2006 to 2010 he hosted a radio show, The Brian McKnight Morning Show with Pat Prescott on KTWV The Wave in Los Angeles, CA. The show was briefly simulcast on KHJZ-FM, Smooth Jazz 95.7 The Wave in Houston, TX from 6AM-9AM CST.
On January 26, 2009, McKnight hosted "The Brian McKnight Show" from 7PM-Midnight on 98.7 KISS FM in New York City.
In 2009, he appeared in the second season of Celebrity Apprentice. Each celebrity played to raise money for the charity of his or her choice; McKnight elected to play for Youthville USA.
From September 2009 to May 2010, McKnight served as the media personality and hosted  The Brian McKnight Show, a late night talk show billed as a combination of talk and variety, aired in syndication. The show was cancelled on May 29, 2010 after one season.
On March 31, 2011 McKnight sang the National Anthem for MLB Opening Day in Cincinnati, Ohio with his sons Brian, Jr. and Niko. He had previously sung the National Anthem for the 1997 NBA All-Star Game in Cleveland, Ohio, Game 6 of the 2002 World Series in Anaheim, California, near his Los Angeles home, and the 2005 Major League Baseball All-Star Game in Detroit. McKnight has also made numerous other "National Anthem" appearances throughout his career. On October 22, 2012 McKnight sang "God Bless America" in the 7th inning of Game 7 of the National League Champion Series in San Francisco, California.
On April 23, 2012 McKnight posted to YouTube "If You're Ready To Learn", which has been characterized by Billboard as a "filthy jam." Billboard selected this lyric from the work to quote: "Let me show you how your p---y works/Since you didn't bring it to me first."  Other media outlets such as MTV, the Toronto Sun, and NewMediaRockstars  have also written about McKnight's recent, more adult-orientated efforts.