Not so much into shooters, so this is far from the smartest out there, but FFX's Sanctuary Keeper deserves honorable mention. Sure, Seymour has all these powerful combinations every time you fight him, but they always happen in the same order (eg: the dreaded Seymour Flux will use 2 Lance of Atrophy/Full-Life Combos, Cross Cleave, and repeat). SK cannot be predicted so easily. He heals himself when he's low (for 9999!). He Esunas status ailments and Disables status buffs. Photon Wings inflicts a seemingly random combination of ailments plus damage to everyone.
Even better, SK takes into account which buffs/debuffs are actually dangerous to him and which ones are not. Blind him and he won't bother with Esuna since his attacks aren't physical. Mute him and he will. Smartest JRPG enemy, at least.