McKnight was born in Buffalo, New York. His musical career began in childhood when he became a member of his church, NY choir and a band leader for his high school, Sweet Home High School.
In 1987, McKnight's older brother, Claude McKnight III, and his band, Take 6, signed a record deal with Warner Brothers. This encouraged McKnight to shop his own demo tapes and by the age of 19, he'd signed his first recording deal with Mercury Records subsidiary, Wing Records.
In 1992, Brian McKnight was released and was followed by two more albums for Mercury, 1995's I Remember You and 1997's Anytime. Anytime sold over two million copies and was nominated for a Grammy. In 1998, McKnight moved to Motown Records.
In 1997, McKnight recorded "Remember the Magic" for Disney World's 25th anniversary. In 1999, he released Back at One - his second release from Motown; after the Christmas album Bethlehem. Back at One sold over three million copies.
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Throughout his career he has collaborated with a variety of musicians including Mariah Carey, Sin Bandera, Mase, Sean "Puffy" Combs, Mary J. Blige, Justin Timberlake, Nelly, Vanessa Williams, Ivete Sangalo, Kirk Franklin, For Real, Canibus, Quincy Jones, Boyz II Men, Christina Aguilera, Regine Velasquez, Shoshana Bean, Gordon Goodwin's Big Phat Band, Rascal Flatts, Talib Kweli, MJG - of the Southern Rap duo Eightball & MJG - Josh Groban, Justin Bieber, Ashley "Awesome" Speelman and CeCe Peniston.
In 2004, McKnight, co-wrote with Australian Soul artist Guy Sebastian the song "Wait" from the album Beautiful Life.
McKnight plays nine instruments: piano, guitar, bass guitar, drums, percussions, trombone, tuba, flugelhorn and trumpet. His music production sensibilities especially his piano based pop ballads, background vocal recording and melismatic voice inflections all draw heavily from James Ingram. 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 at one time simulcasted on KHJZ-FM, Smooth Jazz 95.7 The Wave in Houston, TX from 6am-9am CST, but this station has changed its format. On January 26, 2009, Brian McKnight hosted "The Brian McKnight show" from 7PM-Midnight on 98.7 KISS FM in New York City.
From September 2009 to May 2010, The Brian McKnight Show, a late night talk show premiered in syndication. The show is a combination of talk and variety. The show was cancelled on May 29, 2010 due to low ratings and will not return for a second season.