* The episode "Twisted Sister" is utterly heart-wrenching. The girls try to make a fourth Powerpuff Girl, and because they substitute some ingredients, their new sister Bunny turns out a little... special. She tries very hard to fight crime, but never gets it right... [[spoiler: until the end, where she saves her sisters and then explodes. The other three girls feel horrible, because the last thing they told her was "Bunny do bad!" and that she wasn't cut out to be a Powerpuff Girl]]. Even TheNarrator cried as he was [[DownerEnding closing the show]].
-->'''Bubbles:''' She was good after all. ''We'' were the ones who were bad.
** This particular tear-jerker was so potent that it was even used in ''PowerpuffGirlsDoujinshi'' as part of Blossom's DarkAndTroubledPast.
** Also one of two examples of [[spoiler: KilledOffForReal]], and of those two, this is the only one where this is concrete (the other is the episode where this is merely implied is "Knock It Off," mentioned below)[[note]]'''Narrator:''' *tearfully* And for the first, and final time, the day is saved thanks to Powerpuff Bunny. -Cue HarsherInHindsight picture of Bunny smiling proudly-[[/note]]
* The ending of the episode "Knock It Off". TheProfessor bursts into Dick's factory as he's slowly killing the girls by draining their Chemical X. After he desperately pleads for the lives of his daughters, Dick just decides to kill all of them. As his army of grotesque, monstrous clones take the Professor away, he tearfully tells the girls that he loves them, and they weakly manage to say, "We love you, too," before passing out. After seeing this heartwrenching good-bye, the clones turn on Dick, release the girls, and tell the Professor to run before the factory burns down. He escapes as the factory explodes in the background, killing all of the deformed clones and cries over the apparently dead bodies of his daughters before they come around.
** The part where the clones gang up on Dick. As creepy and misshapen as they were, they didn't deserve to be mistreated by Dick so much...
-->'''Blossom clone''': [[MistreatmentInducedBetrayal You never gave us love!]]
-->'''Buttercup clone''': [[WoobieDestroyerOfWorlds Where was our love!?]]
-->'''Dick''': NO! Stay back! I am your MASTER!
-->'''Bubbles clone''': [[StarWars Only a master of evil]], Dick!
-->'''Dick''': NO, NO, NOOOOO! (''collapses onto a piece of machinery and bursts into flames'')
-->'''Blossom clone''': (''[[HeelFaceTurn releases the girls and the Professor]]'') Get out. [[RedemptionEqualsDeath Before it's too late]]...
** One moment that stands out was a bit earlier, when the Professor challenges Dick to fight him. [[CurbStompBattle It doesn't go over so well.]]
* TheMovie has a pretty dang depressing one. The girls are shunned by everyone in Townsville and called freaks. [[BigBad Mojo Jojo]] tricks them into helping him take over the city, making its citizens hate them even more. Their own ''father'' doubts if they’re truly good, which devastates them so much that they fly off into space and plan to live out the rest of their lives alone on an asteroid. But the most depressing of all is that moment when Blossom looks at the Earth with large, heartbroken eyes, then buries her head in her hands and silently cries.
* In "Tough Love", when Him replaces the town's love for the girls with hate. When the girls (who were then unaware) came to see the Professor, well...let's say it wasn't pretty.
* There's one moment in "Octi Evil" when Blossom and Buttercup are arguing and it slowly pans over to Bubbles crying alone in their room.
* "Helter Shelter", when Bubbles says goodbye to the baby whale.
* "Little Miss Interprets": Upon thinking the Professor wants to replace the girls with new ones, we see Blossom and Bubbles crying. Buttercup fights the urge to cry and eventually gives in.
** The following line from Bubbles:
-->'''Bubbles''': (''to the Professor'') But...I love you...DAD!
* "The City Of Frownsville" has all of the city crying after Lou Gubrious sets his sadness ray on them. Even ends with a tribute to the World Trade Centre of Manhattan New York as it got destroyed on September 11th, 2001. With the caption "This episode of The Powerpuff Girls is dedicated for the memories to the victims of the 9/11 terrosit attack."
* The beginning of "Mommy Fearest" which shows that the Professor, much as he loves his girls, is a very lonely man.
** And later when the Professor reluctantly grounds the girls. You can just feel the tremor in his voice. You can't help but feel sorry for ''him'' too.
* "Speed Demon". The moment it kicks in for the girls that Townsville being in ruins was ultimately ''[[NiceJobBreakingItHero THEIR]]'' fault for being gone so long...
-->'''Buttercup''': No...[[BigNo NOOO]]!
-->'''Bubbles''': (''grabbing both of her pigtails and crying'') WHYYYYY!
-->'''Blossom''': (''sounding absolutely heartbroken'') [[MyGodWhatHaveIDone Wh-what have we done?]]
** Especially as the citizen's chant, "It's all your fault!" over and over again in a CreepyMonotone. Also, these are ''five year old girls'' being put through this!
* The girls' DisneyDeath in "The Rowdyruff Boys".
** The girls coming back to life and telling everyone that they're no longer fit to be heroes because they failed to stop the Rowdyruff Boys and decide that they have no choice but to leave Townsville. Fortunately, Ms. Bellum convinces them to stay.
* A scene from "Neighbor Hood" where Blossom and Buttercup reveal to Bubbles that her favorite TV show is nothing but a set and actors.
* Buttercup full-stop, if you think about it long enough. First of all, the professor had no good reason officially to name her Buttercup other than that it begins with "B". Second, she has no unique power [[spoiler: (and tongue-rolling doesn't count)]]. Finally, nobody really pays her any attention, and even when they do, it's usually when she's in trouble. Even some fans never seemed to care much, instead opting to exploit her misery and attitude for kicks and giggles. Especially since she tends to be remembered as "the bitchy one".
* In the "Boys Are Back in Town" the Rowdyruff are revived by him and being immune to the Powerpuff Girls kisses, they proceed to [[NoHoldsBarredBeatdown beat the crap out of them]] until they are in too much pain to move. The Rowdyruff Boys then go one step too far an put a giant slug down Bubble's dress. After they do that she is clearly suffering and tries to keep from crying which was really sad. On the bright side [[spoiler: this is what motivated Buttercup to find the Rowdyruff Boys' new weakness.]]
* The episode "Buttercrush". It's a little hard not to feel bad for Buttercup when she realizes Ace was toying with her feelings all along. Even during her NoHoldsBarredBeatdown to them, you can tell she's truly heartbroken.
* Did ''anybody'' wanna hug all three girls in "Sweet 'N Sour" when the Fluffy Bunch managed to turn all of Townsville against them with their "adorable" crimes, since the girls were the only ones who saw through the animals' cute exterior?
* The ending of "A Very Special Blossom". Even though it was wrong for Blossom to steal the golf clubs and she did have to be punished for it, you can't help but feel sorry for her.
** How the Professor treats Bubbles and Buttercup after Blossom reveals the golf-clubs. He basically forgets they're even in the room and doesn't even eat the breakfast they made for him.