The Tsunami BETA and Armageddonator from Jets 'n' Guns. Sure, you have to beat the game a couple of times to get them, but holy crap.
Perfect Thanatos in Chaos Legion. Once you level him up that far, he can do pretty much the entire level for you. Bosses included.
Unreal Tournament's flak cannon. Love that thing.
I wouldn't call it overpowered, rather that all the other weapons are a bit underpowered (stuff in this game takes ages to die... and there's so much of it!), but my level-21 character's Triton sniper rifle in Hellgate: London has a damage stat of over 200.
The cannon from the Serious Sam games. Imagine a gun that fires a massive uranium-laced metal ball about a metre across, that rolls across the ground at a medium-fast speed, bouncing off walls. This cannonball deals two rockets' worth of damage to anything it hits - and doesn't stop. No, it keeps going, rolling through enemies until its timer runs out or it hits something it can't destroy in one hit, and explodes massively. Better yet, you can charge the weapon; holding the trigger down for a second or so turns the shot into a faster-moving, burning version that does about three times the damage.
The Type 7 Particle Weapon in FEAR. Its zoom is better than the sniper rifle's, doesn't drift and doesn't close off your screen to a tiny scope-thing. And it kills basic baddies in one hit. I say kills; it turns them into clouds of blood and a scorched skeleton.