The game follows the story a man named Billy West. His very attractive, unbearably beautiful and insanely sexy girlfriend, Annabelle Lane has just gotten kidnapped by a gangster named Godfather Gordon who has taken her to his mansion in New Orleans and Billy is on a mission to save her.
The game is basically a side scrolling beat'em up game. There isnt much platforming except jumping to avoid falling in the swamp water. Although the swamp water is not fatal, it is the alligators that the player should worry about. There is not really any vertical platforming so the game is basically just ordinary side scrolling action rather then alot of vertical movement for the screen. Weapons include a Handgun, a Knife, and a few others so kinds of attacks can vary. There are also shooting sections. These use the NES Zapper and are replaced by the Wii Remote in the Virtual Console release.
Bayou Billy also received some amount of exposure on the Nintendo-themed animated TV series, Captain N: The Game Master where Bayou Billy (modeled somewhat like Michael "Crocodile" Dundee) appears in an episode titled "How's Bayou" voiced by Garry Chalk. Playing on the difficulty of its real world counterpart, Bayou Billy was said to be the one game even Kevin Keene was unable to conquer yet. Mother Brain had Dr. Wily built a robot cat to have Duke lead Captain N to Bayou Billy's world. Captain N ended up meeting Bayou Billy where he learned some tricks from him.
Archie Comics published a comic book series based on The Adventures of Bayou Billy written by Rich Margopoulos and illustrated by Amanda Conner, which lasted five bi-monthly issues dated from September 1989 to June 1990.
The game is mentioned in the Strong Bad Email bedtime story in the "Cheat's Cheatventures in Moses Malone Land" segment as being disapproved by Moses Malone, who hopes the Cheat saved the receipt.