Hamsters and Plague is a tile-based puzzle game. The player moves hamsters by rotating them inside a 2x2 selector. The game proceeds in cycles. At the end of each cycle adult females who have a mate spawn babies, hamsters grow up (eventually dying of old age) and the plague spreads.

In each level, the player needs to survive for a given number of cycles while maximizing their score. Larger spawns score more points but expands the population, increasing the risk to get too close to the plague. Only doctors are immune to the plague but they cannot mate, they are far too intelligent for that.

The game ends in extinction if only one sex is present.