MacDougal says the most Genre Blind line ever just before he gets eaten by a zombie Nastas, and it is obvious that even he thinks what he's about to do is a little stupid, but he does it anyway.
MacDougal: Right, I'm going to wander down that lonely deserted street and get my bag.
That's actually his second (and last) one. His first one is slightly earlier than that. When asked about the situation, he describes himself as a man of science, a man of great learning, and tops it off by saying he hasn't a "fucking clue".
"Have you ever met a Jewish person? [...] Or a British, Catholic homosexual?"
The scene in question, while depressing as hell, gets considerably easier to watch once you've seen Rockstar parody it in-house with Grand Theft Auto V.
Seth all the way. While everyone else are terrified and trying to either flee or fight the zombies, Seth plays poker with them!
Meta-example: You can have John Marston fight hordes of the undead in his underwear; no one will take notice of this and act like it's no big deal.
Same can be said once he becomes a zombie. Unfortunately, the underwear becomes unavailable at this point, so we can't have both.
Riding the Death horse. This one allows you to simply run into one or several zombies at once and *boom* their heads explode on contact. Saving a town from the hordes and running low on ammo? Just mow the brain eaters down while sitting comfortably in the saddle (just make sure you keep a decent speed, lest the zombies will pull you off the horse and quickly have you surrounded).
Bonnie gets some nice Gallows Humor when her father turns and must be put down. "I'd like to say he died doing what he loved, but he never was one for eating folks."
Mother Superior's reaction to shooting a zombie.
Mother Superior: Well, I'm alive, señor. Although, come to think of it, I've committed a mortal sin.
Marston: Claim self-defense. Always works for me.
In Blackwater, a young woman gives you the mission to cleanse the graveyard. Before doing so, she mentions how her mother rose from the grave and ate her father, insisting he was a good man... even though she lists off a very long description of his sins in the process. John, of course, just rolls with it. The capper is as he's leaving:
Young Woman: If you see my uncle Mordecai: burn 'im! Burn 'im real good, y'hear?!?
West Dickens: Uh, because we'll team up and fight the forces of darkness together?
West Dickens: Because I've got something you want! Trust me you cynical bastaaard!
John: *gives a long-suffering sigh and delivers a Boom, Headshot! to the zombie.*
Many players had a good laugh when they first got the blunderbuss. From the game telling you it uses stuffed zombie partsas ammo to the over the top way zombies explode. Executing zombies with the blunderbuss in particular is just hilarious because John stuffs it under their chin and somehow causes their whole body to turn into mist.