It starts in Peoria, Illinois, and by level 3 it moves to Chicago, where Midway is based.
The final level of the Atari Lynx version is Sunnyvale, California, where Atari was headquartered. Especially notable in this case in that the monsters had just spent most of the game steadily heading east and had just destroyed New York.
Creator Cameo: In the opening cutscene, the three humans are designer Brian Colin (George) and programmer Jeff Nauman (Ralph), along with Colin's wife as Lizzy.
Sequel Gap: World Tour, the sequel to the first game, has a 10 year release gap.
2006's Total Destruction was the first game in the series in about five years since Rampage Puzzle Attack. Then, it wouldn't be until 2018, which was over ten years since Total Destruction, for a new game to be released, which would be a Dave & Buster's exclusive arcade game meant to tie-in with the movie.
According to filenames in the PlayStation version of Rampage 2: Universal Tour, Halley's Comet was originally Ganymede, which would have made three Jupiter moons along with Io and Europa, and is still located near the planet on the map.