The title is apparently an ironic reference to this saying by the classic master of irony, Jonathan Swift: "When a true genius appears in this world, you may know him by this sign, that the dunces are all in confederacy against him."
The story is set in New Orleans, Louisiana at the start of the 1960s. The central character is Ignatius J. Reilly, an intelligent but slothful man still living with his mother in Uptown New Orleans who, because of family circumstances, must set out to get a job for the first time in his life in his thirties.
Ignatius is eccentric and creative, sometimes perhaps to the point of being delusional. He has various adventures with colorful French Quarter characters while trying to find jobs requiring little or no work while at the same time trying to further his plans to somehow achieve greatness.