Frank Castle was never shy about killing his enemies, but before he donned the skull on his chest, he limited his kills to the ones sanctioned by the U.S. Government. Of course, all that changed when his family was slaughtered, and he began his one-man war on crime.
The Punisher is all about killing his enemies, but for the most part, those enemies are drug lords, lowlife thugs, Mafia bosses, and the like. Essentially, they are people like all of us, which means they didn't bathe in radiation sometime in the past to become supervillains with immense power.
He's gone up against superpowered people in the past, and his first appearance came in the pages of The Amazing Spider-Man #129 when he was out to kill everyone's Friendly Neighborhood Spider-Man. Castle will hunt down a superpowered bad guy (or hero) when it proves necessary, and thanks to the Marvel Multiverse, that means the Punisher has wasted quite a few superheroes and villains.
Granted, the best stories about Castle killing super-folk are the ones focused on the heroes he wastes for one reason or another, and he's killed quite a few over the years. Of the many powerful players, he's taken off the board; these ten are some of the most powerful.