Scum Labs is testing a new drink called 'Scum Soda'. However, all thirty test subjects that drank it have transformed into angry, hulking monsters! Most of the monsters have been contained in cryo-tubes and hidden within various cities. However, some monsters, such as George, Lizzie and Ralph, are still free! It's up to you to tear down cities and find the hidden monsters.

Rampage: Total Destruction is an update to the arcade game Rampage. In it, you play as one of thirty furious monsters as you make your way through cities, destroying buildings and eating people for health. Destroying buildings builds up your "Rampage Meter" - when this is full, you'll become super-powered for a while, and be able to destroy things much more quickly. Each level also has a bonus challenge - such as 'Eat ten mimes' or 'Destroy five trams'. If you complete this challenge, your monster will receive a permanent upgrade, such as a roar attack, or a charge punch. At the tenth level of each city, players face off against a boss character, Dr. Vector - if you destroy his dangerous machines as well as levelling the city, you'll receive a bonus.

A new feature of Rampage: Total Destruction is the ability to climb on the front of buildings. Instead of just climbing the sides and standing on the top of buildings, players can now smash the buildings from the front as well. However, there is an added danger to this - people now hurl objects like televisions out their windows in an attempt to try and stop you.

The game also includes two previous games from the series as a bonus - the original Rampage, and Rampage World Tour. These games are emulations of the arcade versions of the game.