Like in the first Rampage game, the goal of every stage is to destroy all the buildings in each city while avoiding or destroying the military forces. If the player takes too long in destroying the city, jets will fly in and bomb the remaining buildings, ending the stage with a lower score.
In this game, the player has some control over the course of the game. In the first level, Peoria, a tourism billboard cycles through different regions in the country (Northeast, Southwest, etc.). Destroying the billboard when it is showing one of these regions will send the player in that direction. Players may also choose to eat or ignore the "World Tour" powerups and control which country they can visit. After getting a World Tour power-up, the next few levels will take place in a foreign location until a Scumlabs plant is destroyed. However, the most memorable power-up is the purple radioactive waste, which transforms the player into a super monster known as V.E.R.N. The game will not end until every Scumlabs city has been destroyed, which may cause some erratic traveling around towards the end of the game (including multiple world tour trips if the players have missed or purposely kept from getting world tour flags).