Well, yes, frankly pretty much everything from the ground up. The list of ways in which they are similar would probably be shorter.

From the few times I’ve ran it, it focuses more on a case or problem that seems more of this world (e.g. a missing person, a murder, theft). As the investigators dig more into the case, things get more weird (rituals, weird people, hints of magic etc.). The climax is typically a major event that makes no sense to normal logic like a sacrifice taking place to an Eldritch horror or seeing a monster and running. There’s a lot of failure that happens to the investigators as it is very hard to roll well in things you’re bad at (which is more realistic in my opinion) and it uses a percentile dice system. Library use skill is bad? Can’t find the book that just might save your life at the climax. Combat is typically avoided for that reason as taking half your HP as damage knocks you out or worse. Getting stabbed once might lead to you dying very quickly. All this is happening while the investigators are trying to deny the weirdness that is going on to prevent going insane (which today affects gameplay and can yield interesting roleplay).

Overall, it’s a different system in which the investigators struggle to survive and realize how insignificant they are to the universe with fun roleplay. Four out of five tentacles, would recommend.

Edit: minor spelling mistakes

Just to add to that answer, I’d the biggest difference is the grim powerlessness. The players can barely delay the inevitable and most will probably die in the process.

There are way more skills aimed at investigations, and the goal are often more aimed towards a McGuffin that solves the issues, or sometimes the goal is simply to just be able to leave in one piece and hope someone else cleans the mess 😅. (There’s actually a fan story adapted into a RPG called « Delta Green » where you play a secret military tasked with dealing with mythos threats)

As D&D is the epic hero’s journey where Gandalf saves everyone at the last minute, CoC is the horror thriller where the protagonist dies, only a rando side character survives and walks off screen as the dead monster opens its eyes again just before cutting to black.