Voodoo Vince casts the player as a voodoo doll named, what else, Vince. Vince's owner, Madame Charmaine, has been kidnapped by Kosmo the Inscrutiable because of her valuable zombie dust. During the kidnapping, a bunch of zombie dust spills, warping reality. As a one foot bag of straw, it's up to the player to rescue Madame Charmaine and keep the zombie dust out of Kosmo's hands.
Throughout the game the player will have to contend with a variety of bad guys, from alligators and bees to imps and demons. Players can use standard platforming attacks, like a spin and a head dive, but also have magic voodoo at their disposal. To use voodoo, the player hurts themself, thereby hurting their enemies. Players may pull out a big magnet that causes a debris of heavy metal objects to squash them, killing nearby enemies, or they can summon a UFO to attack them with laser blasts.
Each level is littered with different pickups that not only assist players but will allow them to reach 100% completion. Picking up skulls will add another voodoo icon, letting the player use more voodoo powers. Other items will extend the health bar or provide certain powerups.