De Beck was drawing cartoons by 1910. His comic strip Barney Google and Spark Plug first ran in June 1919 in the Chicago Herald and Examiner. The main character, Barney, was initially a simple henpecked husband and avid follower of sports, but within ten years Barney morphed into an urban rascal and natty dresser. The bony and goofy racehorse, Spark Plug, trotted into the storyline in 1922. Barney met his hillbilly friend, Snuffy Smith, in 1934. Readers found the strip a comic relief from tragic conditions of the Great Depression.
De Beck’s style of drawing is considered to be in the classic "big-foot" tradition quite prominent in American comic strips (e.g., The Katzenjammer Kids, Hägar the Horrible, many of Robert Crumb's characters). After DeBeck's death on Veterans Day, 1942, the strip was continued by his assistant, Fred Lasswell.
The expression "heebie jeebies" (a fit of intense nervousness) and "hotsy-totsy" were coined by Billy De Beck for dialogue in his comic strip.