In the swamps of Florida a leak of nuclear waste has led to the mutation of a previously unknown plant species called the Aisuru Flower. Now scientists have launched an expedition to locate these flowers so that experiments can be made on them. The task has been given to one Professor Oddbod who must enter the intoxicated area and collect as many plants as possible. This won't be as easy as it sounds since the radiation has led to mutation of many other species such as the horrific man-eating flytraps and other kinds of monsters that call the swamps their home.

Swamp Fever is a horizontally scrolling shoot 'em up. The player takes control of Professor Oddbod from a top down perspective and has to navigate through the swamps in search for the rare Aisuru flowers. There are 35 flowers and the player gets points for each. The swamp is full of dangerous creatures that the player has to defend himself against with his gun. If the professor comes into contact with these he will lose energy and when all of the energy has been drained the mission has to be aborted and the game is over.