Superheroes just aren’t very interesting if they don’t have a compelling vulnerability - just look at the DCEU's continued efforts to get someone, anyone, to care about Superman. We thus know that every character in the Marvel Cinematic Universe, no matter how powerful, has at least one discernable weakness, but not every Avenger’s weakness has been depicted or, more importantly, exploited onscreen.
Even when up against the strongest villains their universe has to offer, the MCU's heroes rarely have too much trouble coming out on top. No matter how ruthless the supervillain, how deadset on revenge they are, or how complicated their schemes for world domination might be, the baddies always lose.
Maybe their issue lies not in sheer firepower, then, but in the matchups. The Avengers aren't infallible, and there are plenty of villains in the MCU who could make their lives a lot harder in a fight. Maybe by swapping partners, the villains could have had their day.
In the course of one airport skirmish during Captain America: Civil War, Ant-Man very nearly defeats both Iron Man and War Machine. He gets inside Tony Stark’s armor, pulling out all sorts of wires and plugs, and then he explodes James Rhodes with what he thought was a water truck. And that's just loveable ol’ Scott Lang messing around and trying not to seriously hurt anyone. Imagine if it had been someone with those same capabilities coupled with a killer instinct. Imagine if it was Yellowjacket.
Darren Cross had no qualms about taking lives in his quest for power, and he’d be especially eager to snuff out a business rival in Stark. All he’d really need to do is shrink down small enough to fit inside either the Iron Man or War Machine armors, and then he’d be free to plant explosives or release toxic gas or just plain shoot the unprotected heroes within. Stark and Rhodes could be neutralized or worse before they ever had a chance to engage any fire suppressants - and if the conflict occurred pre-Civil War, they wouldn’t have thought to include any additional defenses against miniature saboteurs striking from within.
Whether it be Steve Rogers or Sam Wilson carrying the shield, the character of Captain America has long been defined by sheer willpower. More than Super Soldier Serums or Vibranium accessories, it is heart and determination that powers Captain America (that “I can do this all day” attitude) and sets him apart from all other heroes. But what if that famous willpower was taken away with a single sentence?
Enter Kevin Thompson, also known as Kilgrave and occasionally known as the Purple Man. His pheromonal powers allow him to command others through verbal commands that are irresistible, rendering grit and determination as nonfactors. If Kilgrave told Cap to give up, Cap would give up with no questions asked. Same goes for telling him to hurl his shield into the ocean, run into traffic, or even desecrate the American flag.
There’s no real limit to what the Purple Man could make Rogers or Wilson do, and he’s certainly not one for moral qualms.
The enchanted inscription on Mjolnir reads that “Whosoever holds this hammer, if they be worthy, shall possess the power of Thor.” That little bit of Asgardian legalese has usually worked out in the Thunder God’s favor, as Thor Odinson has only ever had to consider the worthiness of he and his closest allies, and never even had to think about what might happen if one of his enemies were to get their hands on the mighty mallet. Surely, no villain could ever be worthy of wielding Mjolnir, right?
Carl Creel, descriptively known as the Absorbing Man, wouldn’t even have to lift it. The very nature of his elemental mimicry means that all he’d have to do is touch the hammer to transfer all of its properties into his own body - which, one has to assume, includes that aforementioned “power of Thor.” So, at best, a Mjolnir-flavored Absorbing Man is just as strong as Thor, and the fact that he’d be literally made of mystic uru metal from head-to-toe probably puts Creel over the top in any physical confrontation.
In both the comics and Agents of S.H.I.E.L.D., the Absorbing Man has dabbled in heroism only to inevitably turn back to villainy. Maybe it’s for the best, then, that the Mjolnir of the main MCU timeline was shattered before Creel ever got a chance to lay a finger on it.
The more Peter Parker has grown and learned in the Marvel Cinematic Universe, the more in tune he’s become with his own powers. In particular, his spidey sense (or Peter tingle) proved integral to defeating Mysterio in Spider-Man: Far From Home, and it’s a skill that promises to keep Spidey safe against most villainous threats from here on out.
Most, but not all.
A spidey sense is only as good as its user’s grasp of the reality around them. If that grip were to be broken by a trip to another, different reality - like the Mirror Dimension - then it would be useless. Spider-Man did beat Mysterio by being able to tell what was real from what was not, but where does that leave him in an alternate dimension where nothing is real, and anything could become a threat.
With a simple incantation, Kaecilius - or really any sorcerer with ill intent - could transport Spider-Man to a dimension in which his greatest gift didn’t work and couldn’t protect him. That’s to say nothing of the difficulties of web-slinging through a constantly shifting landscape, and of course all those sharp shards of reality that Parker wouldn’t be able to see coming.