It happened about once in hour in Red Dead 2, I'd be trying to punch someone or ride a horse or walk into a general store and I'd end up brutally stabbing some guy in the gut or shooting a woman in the neck.
I think the worst and the one that will always stick with me though is Morrowind. I played that game for at least 100 hours before I realized it even had a main story quest, I was just running around finding stuff and looking at stuff. Anyone, eventually I started the main quest, I'm now well over 100 hours in on this character and I get to a point where I need to go meet a guy in one of the towns in the Ashlands, and I just can't find the guy. I keep looking and keep looking and ask friends and everything I can think of, and eventually realize I killed the guy some untold amount of hours ago and moved in to his house. I don't remember why I killed him, I was probably trying to rob him and it went bad.
Morrowind had a little pop up when you did this, something to the effect of "you killed an essential NPC, you can either reload a previous save or live in the world you've created" but it was small and it appeared in the lower right of the screen only briefly, I was playing on a 14 inch crt TV, so I could read dick all already. Good times.
Also my first play through of Dishonored was very nearly non-lethal, I had two kills the entire game. One guy got killed by an infected I let out during a mission because I'd knocked him out and hid his body where the infected found it, and the other guy was in the very begining, the sewers, and there's a guard you have to get passed. I knocked him unconscious, but I threw him in the water before going up the ladder, I imagine he either drowned or the rats ate him. Only two kills the entire game though, which I'm pretty proud of.