The book tells three basic stories, which take place between November of 1907 and late May of 1908. The first story is about Will and Eleanor Lightbody. Eleanor, a fan of Dr. Kellogg, drags Will to Kellogg's sanitarium. Hoping to improve his marriage, Will goes along but is constantly filled with doubts about Kellogg's health methods. The second story is about Charlie Ossining, a man who gets into a cereal business scheme with a man named Bender. The third story is about Dr. Kellogg himself; how he runs the sanatorium and of his growing irritation with his adopted son, George.
The title comes from an actual booklet called The Road to Wellville written by C. W. Post, a former worker at the sanitarium. Post used to give out his booklet in boxes of Grape Nuts cereal. In the novel, Lightbody brings up this phrase and invokes Kellogg's wrath.