Favorite or most peculiar cases in games where you play against something or someone that can't be defeated at the start of the game?

[Anoobis]

I liked Bowser with the Star Rod in Paper Mario. The whole game being a build up to the rematch with him gave it a good feel.

 

[ENNOEA]

First encounter with Batman in Suicide Squad: Kill the Justice League. The game nosedives after.

 

[DanCalibur]

Nier Automata, ending E, Square Enix Marketing Division.