Assassins Creed: The hidden bade.
This insta kills any target when used properly. AC2 improved it's use which made it more overpowered.
Assassins' Creed 2: Dual hidden blades.
Self explanetory.
Dead Space 2: Contact beam.
The alternate fire will kill almost any enemy around you, and slow down whatever it doesn't kill.
Resident Evil 5: Rocket launcher.
This will one shot anything, even the last boss. Infinite ammo can be unlocked for it.
Reckoning: Meteor.
This spell is insanely overpowered. It will one shot an entire group of enemies and most bosses.
Human Revolution: Hacking.
Not only is it a requirement for a few missions, but it's the most useful thing in the game.
Star Wars the Force Unleashed: Force
This can be used to literally throw an enemy off the map.