the unreal tournament redeemer. why? you launch an actual nuke into an often tiny level. just about gurantees you will kill every enemy. not to mention a fly-by-wire mode so you can guide it right into them, but there however is a drawback as more often then not you will kill yourself along with everyone else, but often worth it.
max rank Ball Lightning from Baldur's Gate Dark Alliance one. a few castings of this kills everything, even in extreme, short of the final boss, only because she is immune. In fact this spell is largely how I got through extreme.
Max rank empower + max rank enveration in Dark Alliance 2. I clear rooms so fast with that spell, especially if I toss in a max rank Claws of Darkness.
the spells Slow Time and Physical Shield in Fable. They just break the game, especially if you max both and have plenty of mana and mana potions. Enflame was one you could just rapid fire abuse. the 2 one one evil one good circle of annihilation spells from lost chapters.
Beserk + multistrike was another disgusting spell combo.
I also say force storm in KOTOR 2, and while less damagine, force wave as well. I mean still high damage and they are rendered helpless against your awesome onslaught.
Thor's North winds and rage in Marvel: Ultimate Alliance giant tornado sucks up enemies, damages them constantly, and they can't fight back, while also leaving them ripe to be slaughtered with Thor's lightning, and Thor's lightning just peels bosses apart.