In Carmilla the Series season 1, Laura kills the Dean, apparently a thousands-of-years-old vampire by dropping a rock on her head. It doesn't stick, because the Dean is actually a god.
In the "Dark Dungeons: The Movie!", Debbie ends up summoning Cthulhu by playing too much D&D and in the end she defeats him through the power of prayer.
In The Gamer's Alliance, the heroes of the Grand Alliance work together and defeat Nergal, the God of War, in combat.
In the Crinoverse, this happens a lot. The final Chicago Avengers adventure had the heroes facing off with Omega, a being who destroys entire universes. First his armor is blown off, and then he's punched so hard he explodes.
In the Whateley Universe, Sara Waite fights The Kellith in dreamspace with a knife. And wins. Even if Sara Waite is The Kellith, or one is part of the other, or they're a duality, or something.
It actually makes sense in context: the 'Kellith' in the dream represents the magical brainwashing her supposed high priest was trying to inflict on her. Of course, that technically makes it not quite an example of this trope — but then the Whateleyverse also has Tennyo, who apparently eatsEldritch Abominations, demons, and the like. (The jury's still out on whether she counts as one herself.)
In The Salvation War, this trope is definitely in play. In Armageddon?, the human race kills off Satan and in PantheocideYahweh, the entity behind the Abrahamic deity is next on their list. Powerful as heck and incredibly long-lived (functionally immortal against old age? Maybe), but not invulnerable...
As it happens, Yahweh was punched out by the Archangel Michael, but the human race did manage to punch out Uriel, the Angel of Death though.
"But this was the House of Red Fireflies, the greatest whorehouse in the world, and the mistress was a plump, matronly woman who had once killed a god with a broken beer bottle, and she looked at the fish, and she nodded."
In Marvels RPG, the Earth's heroes defeated theGalactusSwarm, being the first species in the universe to complete this task. Generation X defeating Nyx had the same effect.
In the second season finale of Marble Hornets, Jay is sleeping inn his hotel room when he hears Jessica scream from the adjoining room. He jumps up to help her, but then stops and turns around. The Operator has materialized into his room behind him. Jay pauses for a minute, as if considering whether to run away or not, but then just takes thepath of greatest awesomeness and tackles the Operator out a window.
In the famed creepypastaRussian Sleep Experiment, the best defense against the physical embodiment of mankind's daytime fears is found to be a TT-33 pistol.
In the Grand Finale, Rainbow Dash, after coming Back from the Dead and causing reality to reset with a Sonic Rainboom, ends up defeating Discord. Possibly justified since she used the Sword of the Holy Titans summoned by Twilight, which Twilight Prime considered about the only spell that may have been effective against Discord's father Appelox if they could've found someone to wield it.
The SCP Foundation is devoted to containing and studying Cthulhu-grade anomalies that threaten or endanger human sanity, existence, and reality as we know it merely by existing.
There are at least two subversions: SCP-343, who is literally omnipotent and only contained voluntarily, and SCP-2317, whose containment procedure is all just a farce and whom the Foundation has utterly given up on stopping.
And when they actually have to kill one of these uber-creatures? At least in the case of a Reality Warper, a little distraction and a good Sniper Rifle tend to work wonders. They have to know you're there to defend themselves from you, after all.
In 'The Camping Webisode' of DSBT InsaniT, Alex makes a mention to Killer Monster of all the powerful beings he and the others defeated in the past, not fazed by Killer Monster's threat.
Alex: We have taken out mismatched freaks of nature created by ancient serpents, mad scientists with powerfull monsters under their command, and demons who can take over the planet! You don't think we can kill some fire-breathing beast?!
In Worm, Taylor manages to essentially bully a nigh omnipotent world destroying alien to death. By targeting Scion's psychological weakpoints, she drives him past the Despair Event Horizon, and he allows himself to be killed.
In the Steve Poling short story ''Southern Fried Cthulhu,'' a Cthulhu makes the fatal mistake of invading a southern redneck town. After driving half the townsfolk insane, a handful of those lucky enough to have been shielded from his mind-control rays kill him with tinfoil hats, molotov cocktails, shotguns, and a batch of thermite— then slice him up and fry him. Then they get a hunting license to go after more...
Dreamscape: Keela instantly kills the Master of the Dammed by simply shattering his scythe in the flashback in "Tale of the Unworld".
In The Nostalgia Critic special "You're a Rotten, Dirty Bastard", the Critic does this to Roger the angel three times. When he first finds Roger in his home, he punches him in the face thinking he's a Jehovah's Witness. The next time Roger comes up to him, he punches him in the groin so hard it temporarily paralyzes him. Finally, at the end, when Roger turns evil and attacks him, the Critic kills him by shooting him in the face.
Noriko Null from Beyond the Impossible does it so often she earns the title Slayer of Gods, killing Demeter is considered completely unprecedented in its universe: not only she’s the first mortal to kill a goddess, she does it with a Mind Rape machine.
In one of the most triumphant examples of Badass Normal ever, Guts from Berserk destroys THE single most powerful entity in the Soul Series, Night Terror. And then he also takes out Inferno and smashes Soul Edge to win the fight.
Also, Kirby, who is 8 inches tall and utterly adorable, absolutely destroys Majin Buu, the most powerful and terrifying villain in the Dragon Ball universe, by blasting him into the sun. Beware the Nice Ones indeed.
Zero manages to destroy Metal Overlord, the very same being who in an earlier episode of the series, managed to destroy Wily and Eggman's entire armies and then the entire world, and whom Super Sonic needed help to defeat in canon.