Deadly Creatures allows players to play as a young male desert hairy scorpion and an adult female tarantula and engage in brutal combat against other arachnids, insects, rats, and reptiles.

The two creatures have different playing styles, with the scorpion's levels featuring more action-oriented gameplay, while the tarantula is more stealth oriented, with less linear levels. The Wii Remote and Nunchuk are used for both movement and attacks, with motion controls incorporated for special attacks and finishing moves, while the tarantula also utilizes the pointer function to shoot webs. New abilities are also gained as the player progresses through the game.

Along with dispatching common arthropods such as pill bugs, crickets, beetles, and wolf spiders, most of which can be devoured to regain health, the player also faces bosses including a Gila Monster, a rattlesnake and eventually a human. The clashes between the creatures are described as similar to monster movies, with a similar impact to battles in King Kong and Jurassic Park albeit on a smaller scale.