After starting his professional career in the 1930s playing piano in the roadhouses of the American Midwest, Henderson's major break came when he was an accompanist on a 1937 MGM promotional tour featuring Judy Garland and Mickey Rooney.

Henderson later said that as a member of MGM's music department, he worked with Garland to learn "Over the Rainbow" during rehearsals for The Wizard of Oz and played piano for her first public performance of the song at a local nightclub before the film was finished.

"[4] After the war, Henderson worked for NBC Radio Network, where he was the musical director for Frank Sinatra's Light-Up Time.

In 1946, Henderson and the Golden Gate Quartet headlined a 13-week summer replacement program on NBC, sponsored by Old Gold cigarettes.

Two albums as pianist for Arbors Records were released in the early 21st century, Swinging With Strings (2001) and Legends, with Bucky Pizzarelli (2003).

Henderson conducted a 1963 recording for RCA Victor of George Gershwin's Porgy and Bess with Leontyne Price and William Warfield, which won a Grammy.

An exhibit highlighting the musician's career and showcasing the medal, "Skitch Henderson: A Man and His Music," was on display at the Smithsonian from January 30, 2005, to March 13, 2005.

The Retro Swing Band at the University of Wisconsin plays arrangements from The Tonight Show and the BBC Dance Orchestra included in the Skitch Henderson Collection at the Mills Music Library.

From 1972 until his death, Ruth and Skitch Henderson owned and operated The Silo, a store, art gallery, and cooking school in New Milford, Connecticut.

Henderson was indicted on July 2, 1974, on charges of tax evasion for the years 1969 and 1970, concerning claims about the value (allegedly $350,000) of a music library he donated to the University of Wisconsin–Madison.