I've had to put some thought into this, and sadly I've come to the realization that there is no real bad guy from video games that I have enduringly hated. It might have something to do with political and moral differances between myself and the general sentiments of writers, but I don't think it's really that. I think what it comes down to is that I think video game writers don't have the guts to make any really convincingly evil characters. Of course it might just be the games I've played or how I've analyzed things.
To cover one paticular bad guy that seems popular, my thoughts on "Handsome Jack" are a bit diffrant from most people. Oh sure, he's "evil", in a comedically selfish "trying too hard" sense as people point out (which makes him unbelievable to begin with) but on top of that his big "bad guy" moments that upset people don't quite click with me. People will go off about what he does to a couple of the classic Vault Hunters, but remember "Borderlands" is a game where your characters are conceptually a bunch of murdering psychopathic jerks themselves when you get down to it, it's a game where you've already been defined as yourself being a selfishly motivated anti-hero, willing to kill just about anyone or anything to profit from your own treasure hunting. A lot of the guys you do quests for are evil psychopaths themselves when you get down to it, at best being entirely amoral, I mean really think about characters like Zed, Moxxi, and a certain Russian bus driver who also happens to amorally run a planetary gun running operation, and these are the guys you work for/take money from. Not to mention all the psychopathic things you just do as a matter of course, some of which the game rewards you for (specific ways of killing, etc...). "Hey look at me, I'm slow roasting a bunch of bandits", or "look at my exps for head and nut shots!". It's great fun, but at the end of the day when another really bad person who is just as exagerrated as they are comes along and does bad things to them, how much sympathy am I supposed to have? It's fundementally one psychopath doing horrible things to another... it's like ruthless gang bangers killing off ruthless mobsters (or vice versa) everyone is involved is bad, there are no words for how little I care if one of these guys pulls another one's eye out with an ice cream scoop, knowing the victim is just as bad and has probably done similar things.
Or I guess you could say when I play Borderlands I put it in a similar mental vein as playing Grand Theft Auto, sure I empathize with the guy I'm playing to some extent when I play them, but do I feel any objective sympathy for bad things happening to these guys, or learning that a former game protaganist might die violently in the intro to another game in the series? Not really. The game it fun, but at the end of the day the death of a mass murdering psychopathic scumbag isn't something I can get all choked up about. In a game based around playing how utterly wrong every aspect of it is for laughs, it's hard to show much empathy. Handsome Jack is bad, but is he any worse than some of these characters? Seriously think about this one.
When it comes to other video games I guess what it comes down to is that too many bad guys are evil "just because" or justified as being "insane" because there is no other way to justify what the plot requires of them, missing the point that REAL insane people have reasons for what they do, they just aren't good ones or might be detached from reality, but they are usually understandable if you understand who you are dealing with. It was a cool idea decades ago for justifying a uniquely unpredictable enemy like "The Joker", but to be frank it's overused, and to be honest if your not "The Joker" generally undefined "he's crazy" doesn't work, and evem "The Joker" has gotten so unreal that I can't muster much genuine hatred for the character.
When they try and come up with a motivation for a bad guy that makes sense, oftentimes they try and include some moral statement about "the end not justifying the means". A point I intensely disagree with as many people might know, and oftentimes it goes back to the entire "trying too hard" thing, because in some cases I wind up seeing the bad guys as the anti-heroes, especially when the protaganist you control has no real plan to deal with the problem the "bad guy" is addressing ruthlessly, operating entirely on a principle of "not this way", and the game never following through on having to solve those problems by ending on a high note before anything could come to a head.
When it comes to attempts to create hybrids, like mad doctors and scientists (which people mention) again it's a situation where it generally doesn't get believable enough to get me hating them. Sure, it's true that doctors and scientists have done grotesque experiments on people in the past, but usually with understandable motives, Even Doctor Mengele didn't chop people up for stupid reasons, and the dark side of all of this is that the few people they horribly killed really did lead to developments that saved millions of lives. Even today there is some academic debate on things like this. In a video game the evil doctor doesn't have any real motive for what he's doing, it's just general nebulous "experiments", or something unbelievably dumb like "well, I'm experimenting with pain thresholds for lulz, since I have nothing better to do". How can I muster any genuine feeling for what is such a hollow cartoon character, it's simply more gun/spell/superpower fodder before I move on, the justifications are weak that I don't think of the character as anything worthy hating, rather than simply a themed boss fight to get past.
There might be some exception I'm not thinking of, but the bottom line is that the gaming industry doesn't seem especially good at making bad guys to me. You wind up with too much poorly thought out posturing, or a snively whiplash cartoon character you can't take seriously.
Also when it comes to the whole "end justifies the means" thing, especially as it applies to fantasy, before anyone jumps on me, I'd remind you of why "Watchmen" is such a classic story. The "bad guy" in that story is a murdererer, having casually killed a number of people, and in possesion of dubious santity. He winds up basically taking over the world. Pretty much classic super villain stuff. The thing is though that in doing so he saves the world, preventing a global war between super powers. If the good guys, operating on higher moral principles, actually stopped him, the result would have been global decimation, it burns, but at the end the bad guy is right in saying that they actually accomplished more through their failure than all of their successes up until that point. In more than a few cases in video games I feel like my heroes in the role of Night Owl, Rorscharch, and Silk Spectre, managed to actually stop Ozymandias in the 11th hour and thwart his plan... under the same set of circumstances, we prevent an act of mass murder but the central problem he was addressing doesn't go away, the game ends on that trimumphant note, but only does it by not going far enough ahead to show that a trillion or more people die and civilization as we know it die in exhange
for the paltry millions I saved....
Of course I do tend to overanalye things, in a lot of "Star Wars" inspired fiction when the pluky rebels win I always wonder who actually takes over once the "Evil Empire" or it's analogy is over with, especially if the Rebels were a diverse group of independant factions who all generally only agreed on not liking the bad guys, but now are all going to want to pursue their own agendas, and probably cause even more war and bloodshed than the "evil empire" that at least brought stability. In many such cases I've always kind of thought replacing "the evil emperor" with a more benevolent emperor is the way to go, so as not to lose the stability and infrastructure but you know... over analyzation. I know the EU stuff for Star Wars in paticular focused on this to some extent (and illustrated a lot of my points in a way), but before that I still remember at like 14 or 15 wondering if Mon Mothma was now the new Emperess, and what qualifications she had that convinced anyone she would be better than Papaltine, since at least as far as the movies went she didn't do much of anything to sell you on her qualifications to do anything but kind of stand there and maybe hand out medals....