Brown was born in Reinerton, Pennsylvania. After graduating from New York Military Academy in 1932, Brown attended college at Duke University from 1932–1936. There he led the group Les Brown and His Blue Devils, who performed regularly on Duke's campus and up and down the east coast. Brown took the band on an extensive summer tour in 1936. At the end of the tour, while some of the band members returned to Duke to continue their education, others stayed on with Brown and continued to tour, becoming in 1938 the Band of Renown. A few years later, in 1945, this band brought Doris Day into prominence with their recording of "Sentimental Journey". The song's release coincided with the end of World War II in Europe and became the unofficial homecoming theme for many veterans. The band had nine other number-one hit songs, including "I've Got My Love to Keep Me Warm".
Les Brown and the Band of Renown performed with Bob Hope on radio, stage and television for almost fifty years. They did 18 USO Tours for American troops around the world, and entertained over three million people. Before the Super Bowls were televised, the Bob Hope Christmas Specials were the highest-rated programs in television history. Tony Bennett was "discovered" by Bob Hope and did his first public performance with Brown and the Band.
The first film that Brown and the band appeared in was Seven Days' Leave starring Victor Mature and Lucille Ball. Rock-A-Billy Baby, a low-budget 1957 film, was the Band of Renown's second and in 1963, they appeared in the Jerry Lewis' comedy The Nutty Professor playing their theme song "Leapfrog".
Brown and the Band were also the house band for The Steve Allen Show (1959–1961) and the Dean Martin Variety Show (1965–1972). Brown and the band performed with virtually every major performer of their time, including Frank Sinatra, Ella Fitzgerald and Nat "King" Cole. The annual Les Brown Big Band Festival, started March 2006 in Les' hometown, features area big bands preserving the songs of the big band era. At the 2012 festival celebrating the 100th birthday anniversary, the town of Reinerton renamed the street near Les' birthplace to Les Brown Lane.
Les Brown Sr. died of lung cancer in 2001, and was interred in the Westwood Village Memorial Park Cemetery in Los Angeles, California. He was survived by his wife Evelyn, son Les Jr., and daughter Denise.
His grandson, Jeff "Swampy" Marsh, co-created the show Phineas and Ferb.
Brown was inducted into the North Carolina Music Hall of Fame in 2010.