4. All of Them (Dead Island)
Ya know, it may be a little unfair your average person would be so terrified at the prospect of an actual zombie uprising, they probably would be pretty helpless if you tried to lead them to safety during an undead apocalypse. Doesn't matter whether it's in a mall or a tropical island people just aren't equipped to deal with it, emotionally or mentally. Still, that doesn't make it any less frustrating to see an NPC stop dead in their tracks while a horde of zombies descend on them for practically no reason, then decide to run at the zombies, or wander off-route entirely while you desperately try to keep the hands of the newly-risen off their fragile, vacation-tanned skin.
3. That Fucking Nuke Truck (Blast Corps)
I'm not sure if it's ever given a proper name, but that's not important, because everyone who played Blast Corps will probably recognize it by "that fucking nuke truck" the truck that drove in a relentless straight line at the same speed, regardless of what was in front of it or the fact it was carrying some EXTREMELY sensitive nuclear missiles. You're stuck in a variety of vehicles to destroy all of the buildings and obstacles that the fucking nuke truck might run into, while unable to just I dunno turn on the thing's parking brake or give it some flat tires or ANYTHING that would stop it from ramming into danger for no reason. The end result is that you have to destroy pretty much every building on Earth in order to save everyone on Earth, often using incredibly dumb vehicles (lookin' at you, Backlash) to get the job done. Frankly, if humanity's dumb enough to unleash a fucking nuke truck on a set path and then realize WITH SECONDS TO GO that, oh yeah, better get rid of those buildings, maybe they deserve a nuclear winter.
2. The Alchemist (Spyro 2: Ripto's Rage)
The only good thing about the Alchemist escort mission in Spyro 2 is that it's optional. Because other than that, it's a laundry list of everything that can possibly be wrong with escort missions. The Alchemist who must be pretty smart to have invented some magic potion stumbles directly through a field of unkillable rock monsters without slowing down at any point, forcing you to run back and forth, trying to knock said rock monsters onto their rock-asses long enough for the dopey Alchemist to bumble through. That Alchemist guy, by the way? Dies after one hit. None of this would be unforgivable, except he takes the most circuitous path possible to get to his end destination going past every single individual enemy to get to a spot that was about 20 feet away. And what do you get as a reward? Another orb. Makes you miss the days that dragons would spend their time burning down villages and terrorizing peasants, instead of babysitting directionless life-hating scientists in exchange for orbs.
1. Natalya (GoldenEye 64)
Let's get one thing clear: Natalya is the worst, but it's not out of the blue. She's a slow hacker ("She doesn't even have access to the firing codes!"), which makes sense, given her hands are blocky cubes without fingers. She's incredibly weak, and has a tendency to run directly into the line of fire, which also makes sense, since her whole life has been turned upside down and most of her friends were horribly murdered in front of her. I mean, anyone else in that scenario would probably have something of a death wish too. If these were the only things that made her an annoying escort NPC, she'd still be on this list, but much earlier on.
The real problem with Natalya is that she won't let you kill Boris. Boris, the traitorous, not-very-invincible hacker extraordinaire, who has betrayed her several times at this point and is trying to help a madman cause a worldwide financial meltdown and kill millions. That guy. She won't let you kill him, and will abandon you and cause you to fail the mission if you do (thus dooming millions to death and ensuring Trevelyan's plan will succeed). Why? Boris is an evil, useless dick who is actively trying to ruin the entire world. Also, he's a ghost. He literally walks up to a vent and fades away into nothingness if you don't kill him, which if not an actual ghost, is definitely somewhere on the specter spectrum. So, as a result, you're stuck desperately trying to protect a suicidal, insanely-loyal, cube-fisted level 2 programmer and her evil poltergeist friend.
Well, at least you don't have to carry her through water.