As with the Nightmare Fuel page for this franchise, that this is a generally light-hearted comic aimed at young children makes the sad moments all the more impacting.
- Every single thing about Mariana, originally a star who came down to Earth due to an intense desire to live among humans, achieving this by being born as Chuck Billy's little sister... who eventually falls ill and passes away while still an infant.
- When Monica finally gets a date with Luca, she ultimately screws it all up and Jimmy Five finds her crying about it. Following Monica lashing out at him and Jimmy revealing his pet chincilla died the night before, Monica opens up to him about all the crushes she's had across the comic's run and how none of them ever worked out. It's one of the few times Monica displays this kind of insecurity and one of the fewer occasions where it is NOT Played for Laughs.
- On that matter, the very story about Jimmy Five (and Sunny's) chinchilla mentioned above, Caramel. Anyone who's ever lost a pet, especially as a child, can relate to Jimmy tearfully asking his mom why she took Caramel away, and to bring her back. If one doesn't cry from that, they will while reading the ending, in which Jimmy comforts Sunny by saying that according to his father, every little pet has their own heaven to go to. The last panel has Jimmy and Sunny looking confidently at the night sky in which, drawn with stars as if they are constellations, the two of them plus Caramel (in the narrator's own words) "play together among the stars".
- Smudge is called for a soccer team representing his whole neighborhood and he ends up being put in as a Goalkeeper when he is a striker. Logically, he does a poor job at it and ends up ostracized by his own team, bar the boy who called him in the first place. It hits the poor kid HARD.
- One Bug-a-Booo storyline is a spin on the movie Ghost, following the original story beat-for-beat, with the addition of a rival named Ted, who is essentially a Composite Character combining the roles of Carl and Willie. Basically, Ted murders Sam and then proceeds to harass Molly in the most lecherous and violent way a comic book for children can allow. Lady MacDeath herself, in the role of Oda Mae, intervenes, giving Ted his comeuppance and telling Molly how much Sam still loves her. Tragic enough, but it gets even worse, as we get to see what happens to Molly after these events, as she never forgets Sam and grows old without ever falling in love again. When she dies of natural causes, she is overjoyed that she will finally be able to see him again... only he is being reincarnated at that exact moment, leaving them separated for eternity. What Do You Mean, It's for Kids?
- The main 4's reactions when faced with the fact their warrior parents will have to be sealed by Yuka until they complete her trials across the 4 Dimensions is gut wrenching.
- It took 36 issues for Monica and Jim's Relationship Upgrade, and it ends up on a sad note. They rushed in the relationship as part of Monica's plan to get Jim to make the big move on her and when Jim finds out, he breaks up with her because he needs to defeat her and Monica cries, feeling their relationship was just another challenge to him and tearfully asks why he needs to feel superior to her. He then reveals a MASSIVE inferiority complex in regards to her and that he doesn't want to be above her; He wants to be her equal and feels that unless he surpasses her, he'll never feel worthy of her. It really puts the Zany Schemer's character on a whole new light.
- From the same issue and the ones that followed the above moment, the main 4's friendship suffering from Monica and Jim's Belligerent Sexual Tension moments.
- Since Monica and Jim's first breakup, Jim has been on a slippery slope into mean-spiritedness that culminated in him acting like a complete tool to Monica and Nick Nope in Issue #68 that prompts Monica to kiss Nick Nope in front of him and the whole gang when she realizes how supporting and encouraging he is to her. In the following edition where Monica is struggling to decide who she wants to be with and Jim, remembering her plan from 33 issues ago, thinks everything from her kiss with Nick Nope is a plan to make him crawl at her feet again and when she wants to talk to him about her confusion, Jim lies and tells her that their moments were just flings and that he doesn't care if she has feelings for Nick Nope, hoping to turn the tables on her when in reality, all he did was hand Monica to Nick Nope on a silver platter. The tearjerking part comes when, after a brutal call out on Maggy's part, it finally dawns on Jim just what exactly he just did.
- When Smudge temporarily gets Captain Fray's corrosion powers, the whole town and his friends turn on him because of the damage his powers cause despite him trying his best to use them for good.
- Nick Nope seeing that Monica wasn't completely happy with their relationship as a result of him always wanting to be different and then deciding to break up with her.
- Jim's Heel Realization after receiving a Breaking Lecture from Future!Sunny.
- An unexpected source for this is Captain Fray after the Inverse Tower arc. His parents died in a landslide in his childhood and he made a Deal with the Devil to save his life there in exchange for being cursed with powers of corrosion and decay. Upon reaching adulthood, the devil he made a deal with returns, demanding he bears The Curse of Pestilence. He is forced to do so because if he refused, the devil would have gone after Smudge, his nephew. Throughout all years the comic has been going on and the chronologic 10 years from the comics to the manga, Fray was fighting his nephew without being able to do a thing to stop it. Even worse, in the Bad Future, Smudge ends up getting his powers anyway, making his a Senseless Sacrifice.
- Irene's character as a whole, since her debut chapter. All she wants is to be friends with the gang but Monica goes out of her way to keep her isolated out of petty, irrational jealousy.