Ink City/Tear Jerker

Towards the end of the infamous Benson/Mordecai/Heloise Log, aka Log #3, Benson squeezing Mordecai's hand as a last gesture of comfort before Hely smashes his head in with a hammer.
The utter breaking of Rigby during Event #1, leading up to the point where, after witnessing Chipotle and Phoenix getting sucked into the Mayor's black hole, he chooses to jump in. Benson's decision to join him is just as depressing.
The end of Log #36, when Jimmy and Hely say their goodbyes as he melts away.
The aftermath of Log #44, wherein Rigby first is forced to try and kill his best friend, then has another nervous breakdown. Again, Benson does not help when he realizes just what role he played in Rigby's latest trauma.
Event #2, aka Superboat goes horribly, horribly wrong. Specifically, this moment, where Megamind's fight with an inky tentacle is derailed upon hearing Roxanne's voice coming from it. The implications are staggering...
- To follow that up, Heloise gets her own shock when she hears Jimmy's voice coming out of the ink monster and Rigby shoves her to her death.
- And then Chipotle gets his own moment along the exact same lines, only with Hely's voice instead.
Yakko's reappearance in the City after being broken. Especially when Dr. Scratchansniff finds him like that...
After hitting it off with Ichigo and learning a bit about how the Great Cosmos function, Megamind asks her who's in charge of black holes. Ichigo has a bit of a breakdown when she learns why.
Phoenix confronting Rigby after learning what happened from Trevor and calling him out on it.
During me1TD0WN's third act, Misery finds her dear friend Thrasher suffering, and tries to comfort him. It ends poorly, as he unintentionally shows her what happened to his world.
Once upon a time, Ink City had a Rapunzel and a Flynn Rider. They adopted an orphan girl, and lived happily... until all three disappeared without a trace. Much later, a new Rapunzel appeared... and the original Flynn returned. Their reunion^{[dead link]} is bittersweet, as this Rapunzel was still in the middle of her first great adventure with him... and wasn't aware of everything that was supposed to come after that point.

Flynn: There is an upside of all this... It's not everyone who gets the chance to fall in love all over again, now, is it?

This IC version of Organ starts out cheerful, but it all spirals downhill when Yakko gets bitten by a zombie.
- And this follow up showing Yakko in his final moments doesn't help either.
- Not to mention the Sequel
Dot and Wakko decide to have a 'Character Development Intervention' on Yakko. How well it ends is still up in the air, but bring tissues anyway.
An otherwise cheery conversation between Legato and Crmsn takes a turn for the worse when Crmsn learns of the tragic fate that befalls another member of the family in the future. Since it involves Birth-Death Juxtaposition, the thread swerves straight into Tear Jerker territory for a while, before swinging back up into the lighter mood.
Hely finds out where the voice in her head is coming from... or rather, who. As well as why they've started speaking to her... and who they brought along to ease the blow.
Yakko gives Dot the full story about his time alone in Ink City.
- Shortly after, Wakko asks him if he feels like they're drifting apart.
An argument between Yosuke and Zorua over her shredding one of his pillows takes a heartwrenching turn when she takes the form of a girl she's seen in his photographs: Saki.
Dot and Ichigo's camping trip is rudely interrupted by the flying pig, pursued by Oscar Mayor. Things get...chaotic, and they both end up getting SLAMMED INTO THE FOURTH WALL.
Despite promising that whatever happens, they'll always stay together, Yakko disappears for a time. Dot does not take it well, and chews out Wakko for not having any clue how to handle it. Wakko shuts down.