He is best known for his magazine cover art for Vogue, Vanity Fair, and Life, but also provided artwork for a large number of advertisers.

He provided artwork for ads for Kum-a-Part jewelry, E. Howard Watch Company, Franklin automobiles, Kuppenheimer clothes, Right Posture clothes, Ohio Electric Car Company, Remington Arms/Union Metallic Cartridge, Durham hosiery, and BVD underwear.

His artwork for Battle Stories was initially produced as a WWI recruitment poster and reprinted as a pulp magazine cover by Fawcett Publications in 1931.

[5] Leyendecker served as the judge in the first Strathmore Water Color Contest, sponsored by the Mittineague Paper Company of Massachusetts.

[7] Leyendecker was suffering from depression and poor health due to his ongoing drug addiction when he died, most likely by suicide, of a morphine overdose on April 18, 1924, at the age of 48.