DeSylva's first successful songs were those used by Al Jolson on Broadway in the 1918 +Sinbad production, which included "I'll Say She Does." Soon thereafter he met Jolson and in 1918, the pair went to New York and De Sylva began working as a songwriter at Tin Pan Alley. In 1925, he became one third of the songwriting team with lyricist Lew Brown and composer Ray Henderson, one of the top Tin Pan Alley songwriters of the era. The writing and publishing partnership continued until 1930. The 1956 Hollywood film The Best Things in Life Are Free, starring Gordon MacRae, depicted the life of the DeSylva, Brown and Henderson team.
De Sylva joined ASCAP in 1920 and served on the ASCAP board of directors between 1922 and 1930. He became a producer of stage and screen musicals. DeSylva relocated to Hollywood and went under contract to Fox Studios. During this tenure, he produced movies such as The Little Colonel, The Littlest Rebel, Captain January, Poor Little Rich Girl and Stowaway. In 1941, he became the Executive Producer at Paramount Pictures, a position he would hold until 1944. At Paramount, he was also an uncredited executive producer for Double Indemnity and The Glass Key.
The Paramount all-star extravaganza Star Spangled Rhythm, which takes place at the Paramount film studio in Hollywood, features a fictional movie executive named "B.G. DeSoto" (played by Walter Abel) who is a parody of DeSylva.
He is sometimes credited as: Buddy De Sylva, Buddy DeSylva, Bud De Sylva, Buddy G. DeSylva and B.G. DeSylva.