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.
10. Captain America
During Marvel's first "Civil War," the Punisher had a little run-in with Captain America after he gunned down two criminals who attempted to join forces with Cap's anti-registration group. Cap immediately began pummeling the Punisher, but he didn't fight back. For Frank Castle, Captain America is his hero, so he wouldn't raise his fists to the man.
That's what went down on Earth-616, but over on Earth-11080, Cap and the Punisher's confrontation didn't end as well. In that alternate reality, a virus swept across the planet, infecting everyone. Instead of making them sick or killing them, the virus turned everyone into cannibals.
The virus infected superpowered folks as well, so Captain America organized a squad of himself, Punisher, Deadpool, and Wolverine in an attempt to stop the Hulk and his faction. When they fail to find the Hulk, the team split up, leaving Cap and Castle alone to fight the Hulk's mob.
Before long, Cap started showing signs of infection, but he still maintained some control over his mental faculties. Realizing he was infected, Cap knelt down on the floor and asked Castle to kill him before he fully turned. Before he pulled the trigger, Castle informed Cap that he always was his hero.