[2] As a boy, he and older brother Fred began performing in live theatre appearing in summer stock and touring with their parents.

He choreographed and starred in the 1913 Broadway musical When Dreams Come True by Silvio Hein and Philip Bartholomae; a piece written specifically for him.

and eventually other productions at major venues across the United States such as the National Theatre in Washington, D.C. Their final collective Broadway presentation was in 1927's Just Fancy, which Santley co-wrote, produced, and directed.

In 1929, Joseph Santley co-directed with Robert Florey the first Marx Brothers feature film, The Cocoanuts, a musical comedy for which he is most famous.

Santley also directed the musical short film, All Americans which featured song and dance numbers relating to nativism that arose in the 1920s.