The game has an 18 rating because despite the fact that it is clearly a cartoon, there is still plenty of sex, violence and bad language. The graphics are very sophisticated, despite the fact it is a 2D side scrolling game, and much of the scenery and environment is either destructible or partially destroyable.
For example, a person that has never heard of South Park may not know what PC principle is, but once he has told his first gag or done his first funny thing, any and all players will understand it and get it. The only benefit that South Park fans enjoy over non-fans (besides the novelty) is that they will get the jokes faster. For example, non-South Park fans will understand references to comic book movies and how they are produced. Every single joke stands on its own, and each reference is as applicable to fans as it is to people that have never heard of South Park. You do not have to be a South Park fan to love South Park: The Fractured but Whole, to understand it, or to play it. Do you have to be a South Park fan to love it?