Johnny Mnemonic is based on William Gibson's short story and a subsequent movie of the same name. The game's plot bears more similarities to the movie than to the original story. Johnny is a courier in a futuristic society, delivering data implanted in his brain. However, the latest delivery is so big that it can kill him if he doesn't download the data. Unfortunately, the only person who knew the password is dead, and members of the Yakuza are hunting for the data and for its living container.

The game consists of live-action video footage and interactive sequences, some of which play like adventure game segments and may contain simple puzzles, while others are more action-oriented. Johnny's bodyguard Jane often handles the fighting episodes; the player can assign buttons to punches and kicks. The adventure parts contain limited exploration and interaction with the environment, and mostly serve to advance the plot.