In The Organ Trail, players must cross a post-apocalyptic United States in an old station wagon in order to reach a sanctuary free of zombies. Players must manage their limited resources, including food, ammunition and fuel for their vehicle, in order to complete their journey and keep everyone in their party alive and healthy.

At the beginning players can choose from a number of characters to play as including a cop from Kentucky, a clerk from New Jersey, or a lawyer from Miami. Each character has different bonuses in gameplay; for example the cop will offer more hours for the player to scavenge for supplies at the beginning of the game but will earn less points if the player beats the game, while the lawyer will give the player the least time to scavenge for supplies but earn the most points.