Callahan became a quadriplegic in an auto accident at 21.The accident happened in Callahan's car after a day of drinking. His car was being driven by a man with whom he was bar hopping.
Following his accident, he became a cartoonist, drawing by clutching a pen between both hands. His visual artistic style was simplistic and often rough, although still legible. It has been likened to that of William Steig, James Thurber, Richard Condie, and Ben Wicks.
Callahan's cartoons dealt with subjects often considered taboo. His black humor may be exemplified by the title of his "quasi-memoir", Will the Real John Callahan Please Stand Up?. The subject matter and treatment of his cartoons shares something with the work of Charles Addams, Gahan Wilson, and especially Charles Rodrigues, although it is much more aggressive than even the Playboy cartoons by these cartoonists.
For 27 years until his death, Callahan's work appeared in Willamette Week, whose cartoons occasionally led to boycotts and protests against the newspaper.