- The split between the heroes has Stan and Kenny pitted against Kyle. When Kenny, Stan and the others jump ship with the plan to overthrow Cartman's team, you can see Kyle looking concerned that two of his best friends are now his enemies by default. What's more, Tweek and Craig are also on opposing sides, and the first time you see the two teams fight, the two are in the front row arguing about their relationship. There's even special dialog if you get them to attack each other.
- As usual, visiting Kenny's neighborhood and place is depressing. He's dirt poor, and his family struggles to just stay alive.
- In the beginning of the game, the New Kid walks in on their parents having a fight. Their mother can later be found in the kitchen, crying.
- The New Kid forlornly eating dinner alone after seeing their parents fighting. It's a surprisingly poignant moment, especially considering that they very rarely emote. It also shows that, despite all their heroics, that they're still just a kid who can't really stop their parents from going at each others' throats. Made even worse because it's essentially your fault: not because of you being born, but because of your supernatural ability to make friends. This scene can be doubly painful for players who've actually been through seeing their parents marriage fall apart, especially on the second night where you can hear New Kid's parents viciously arguing in the next room while you eat dinner.
- Seeing Randy Marsh drunk and needing children to protect him from himself is disconcerting, perhaps even if you dislike him as a character in the series.
- The final time the New Kid's parents appear before the Timey-Wimey Ball starts affecting the plot, the mother is heavily injured and not far from bleeding to death, and the father is strapped to an operating table, naked, and terrified. They still keep arguing with each other throughout, showing that even the most extreme of situations cannot bring them together. Then, it turns out that to progress, the New Kid must kill one of them, either by ripping off mom's arm, or cutting off dad's head with a laser. Yes, really. And the whole time, they each encourage their child to kill their spouse. It's dark.
- If you decide to kill the father, his Famous Last Words are either a Dying Declaration of Hate towards his wife... or him saying that he's scared, and using his last words to tell his child goodbye and say that he loves them so much.
- Either way, it is not just a one-and-done. You have to press A three times, with each instance having the parent in question desperately begging you not to go through with it. And then once you're locked into which parent to kill, the game makes you mash a button to finish the job. and it takes a while to finish that mash sequence too.
- There's a subtle (but no less effective) one occurs during the New Kid's raid on the U-Stor-It facility. Almost every time the New Kid looks up at Professor Chaos (aka Butters) on one of the TV screens scattered all over the storage facility, The New Kid gives a shocked expression, clearly dismayed that they and Butters are fighting on opposite sides. In short: The New Kid is well aware they're forced to fight their best friend, and they hate having to do so. And considering Butters' long history of people treating him as little more than a whipping boy, that's saying a lot.
- For reference, your character almost never emotes outside of combat. Your character still has their usual blank expression even when watching Captain Diabetes dying, or facing the horrors of the genetics lab, or having to kill one of their parents to progress.
- Most of the U-Stor-It mission is nothing but Teeth-Clenched Teamwork between Toolshed and Coon and Friends, and Toolshed makes it perfectly clear that he's only here because he owes you. However, there's a moment at the end where he and Kyle drop the superhero personas and have a brief conversation where it's clear they miss each other. Even when they brag about their respective franchises, one-upping each other with the amount of money they plan to make, it's easy to see that their hearts aren't in it.
- As Played for Laughs as it is, the scene where Super Craig is almost consumed by the "lava" can be surprisingly sad due to the music and the way everyone's lines are delivered. What's especially surprising is that Cartman, the one who takes the superhero game the most seriously and seems to have trouble differentiating it from reality, is the one who's the most desperate to find a way to save Craig from his "fate", even having to be held back by Jimmy from trying in vain to save him.
- Captain Diabetes runs out of insulin and goes into a diabetic shock. Hearing him desperately calling out for his mother and suffering a Disney Death is very hard to watch, especially if you're a diabetic and you've probably suffered the same thing.
- Near the end of the game, you and the others are trapped in Mephesto's labs surrounded by hordes of genetically engineered abominations. About halfway through the level, during a small break before you do your next objective, Clyde breaks down and starts sobbing uncontrollably, saying he just wants to go home. As part of random conversation in the room, the others can try to comfort him, such as Scott saying "It's okay Mosquito, we're not going to die in here. We will survive," Shortly after you leave the room, Clyde posts a photo of himself on Coonstagram with the caption "Dad if you can read this I love you. I'll say hi to mom for you."
- When Dr. Mephesto makes his second reappearance in fifteen years in the game, he is shown with a sprawling science facility with several other geneticists working alongside him, as well as tours, with references to 'Mephesto Tech', but in all of his previous appearances in the show, he's been shown as a recluse working alone with an assistant, Kevin, and on one memorable occasion, his son Terrance, who was the same age as the main characters. The game reveals that Terrance previously died during the series, and that Mephesto has been trying to create clones of him, which he shows off to the main characters. Although he denies it, one could still come to the conclusion the improved facilities are related to his regret over his son's passing, although its implied this was closer to the beginning of the series. (Of note, Kevin is not present in the game in any form.)
- The Buca de Faggoncini restaurant is packed with douchy clients mocking addicts, alcoholics and dysfunctional families, all things that apply to the New Kid. Even when indulging in a bit of escapist fantasy, your problems follow you everywhere.
- If Clyde should die in battle, he'll often mention seeing his deceased mom. There's also something heartbreaking on seeing that his father's bed is the only double bed in South Park to have just one pillow.
- One of the Creek yaoi fanarts can be found in the backroom of Tweek Bros., where Tweek was established as spending much of his time working in the last game. When the player first finds it however, it's covered with a poster. This implies that Tweek himself (or his parents) was the one who put it up, and that Tweek then covered it up after his break-up with Craig.
- Depending on how much you think Cartman cares about the New Kid, his betrayal overall could be considered one hell of a tear jerker. Consider, Cartman has consistently viewed the New Kid as a good friend and protege, with the both of them possessing a bond built on mutual trust and respect. But then he turns on the New Kid by kidnapping their parents as Mitch Conner, and frequently switches back and forward between being Mitch Conner and The Coon, the former being a sociopathic criminal forcing a child to be his key to victory, and the latter being the kid who sympathizes with his friend's situation. The two personas even butt heads whenever Mitch Conner tries to get under the New Kid's skin. One of the most charitable interpretations one could give is that Cartman may be enacting Psychological Projection on himself, forcing himself (in his own Cartman-like way) to acknowledge that he's hurting one of the few people he's ever genuinely cared about and it tears him apart knowing that he can't bring himself to put aside his selfish obsessions for the New Kid's sake. Cartman has lost in his schemes before, but his defeat at the end of the game comes as much more of a blow to him since he not only lost his selfish end-goal, but he knows his selfishness almost cost him his friendship with the New Kid, someone he considered almost as important to him as himself. Of course, after the main story, the Coon is once again a playable character, implying that the New Kid forgives him and still considers him a friend enough to let him work with them again (which is further shown during the later events at the Casa Bonita DLC Sidequest). Even if we interpret Cartman's kindness toward the New Kid as just a ruse, it would just mean that despite New Kid's genuine acts of loyalty toward him, Cartman saw them as just another pawn, and another victim.
Tear Jerker / South Park: The Fractured but Whole