Einsteinian Roulette ends with the real purpose for the HMRC being revealed, the Eater of Stars moving back towards the Origin, the Lurker exploring the end of the galaxy, and HMRC personnel desperately trying to find another universe before the Lurker changes our own enough that life is physically impossible.
Considering the fact that the premise of Survival of the Fittest is 'Kill until only one survives' these kind of endings are pretty much inevitable. Of especial Tear Jerker material is the ending of V1, whereupon the winner visits the families of a number of their deceased classmates. There's also the fact, y'know, that the winner is the only survivor out of the group of 123 kids on the island.
Homestar Runner: In-universe in the first Halloween cartoon, Homestarloween Party, where a scary story is told and each character adds a piece. Strong Sad ends the story by killing everybody off, causing all the attendees to leave crying.
In Dr. Horrible's Sing-Along Blog, Dr. Horrible manages to defeat Captain Hammer and gain entrance into the league. But Penny, the girl of his dreams and the most actually heroic character in the show dies accidentally and is forgotten by everyone except him. And because of this he's left emotionally destroyed
Honorable mention: All About My Dog: Marimo on Youtube. The whole thing is pretty sad, but if the last 5 minutes don't make you cry you have no soul.
Season 2 of The Guild ends with Codex feeling horrible about breaking Zaboo's heart, seeing the guy she liked making out with her married friend Clara, and then finding Zaboo making out with Stupid Tall Hot Girl. Meanwhile, the guild leader Vork has a breakdown, and Bladezz deleted Tink's character, which in this series is just as angsty.
Bonus Stage, after first killing off Rya in a cheap and poorly-executed manner, then went on to have Phil go back in time and murder himself in the first episode, resulting in Joel trying to hang himself, being persuaded to keep going and build a machine to resurrect people, then accidentally killing himself ANYWAY, thus erasing the whole series from time. And this was a CHEERIER version of the episode (the original just cut to Joel dangling from the rope after he decided to give up).
Another example from Cracked: An article about columnist John Cheese trying to quit smoking. It's a very funny but intense recount of his thoughts and feelings during the first day kicking the habit. The sad part is, after a fake editor's note for the final joke of the article, there's a real note beneath it:
Update: John resumed smoking a few months after this article was posted.
Subverted. He quit again, although he still uses patches and gum.
Almost every episode of Happy Tree Friends, however, "Class Act" is probably the most famous example.
Parodied in The Nostalgia Critic's review of Moulin Rouge!, where he realizes that because it's a Moulin Rouge! review, they need to have a sad ending. So he creates one by shooting Brentalfloss, and spends the end of the review mourning him. Then Brentalfloss shoots him from Heaven in revenge.
A few episodes play this straight:
James and the Giant Peach: The Critic doesn't get forgiven and ends up being shot by a lot of guns, though he comes back in the next episode.
The Top 11 Dumbest Superman Moments: Recalling what happened to the actors and the World Trade Center towers makes the Critic miserable and he goes off to kill himself.
The Top 11 Saddest Nostalgic Moments: As the Critic signs off, he gets shot in the head.
A Simple Wish: Mara Wilson herself appears, calling the Critic out on holding child actors accountable for the movies they were in, no matter their age. Critic refuses to relent, Wilsonóto the Critic's utter horroróbegins showing and tormenting the Critic by showing humiliating videos from his adolescence years and now the world has seen them, snarking at them all the while, ending with the Critic screaming out "MARA WILSON!!!!!".
Son of the Mask The Critic is left crying, traumatized and scarred for life by the movie and Satan doesn't grant his request to be put out of his misery, and his daughter goes from childishly cute to horrifyingly ugly, thanks to the movie.)
Catwoman: Halle Berry (played by Orlando) appears and the Critic gets beaten up by her.
Romeo And Julieta: Being based on Romeo and Juliet helps, but even in that the protagonists' deaths at least managed to end the family feud. Here, they're dragged off in the middle of their wedding, hung from a tree, and busted open with a bat. It's pretty clear that the ones responsible won't be getting punished for it, and it's never made clear whether or not they know of the piñata's sentience, so they might not even know what they did.
"The Malthusian Paradox", a British ARG running in late 2012, ends with one protagonist under arrest, the other turning out to have been working for the enemy all along, the kidnapped professor dead, and the antidote to the genetic virus in the hands of some evil third party. And that's with the players being successful at every task along the way... Presumably, that was the *good* ending.
Elrich from The Wanderer's Library is destroyed by its stars, which are then captured and contained by the SCP Foundation at an unknown point in the future. A Hand, An Eye, A Tooth ends with protagonist being killed by her husband for her disfigurement.
In the Arby n' the Chief series finale, things were looking so grim that Arbitur was about to commit suicide but things looked up for him as Claire came back online and promised to play with Arbitur an hour a day. Things were looking up but chief, who just got his voice back, decided he wanted to end it all with a literal bang. the episode ends with Arbitur and the chief saying their goodbyes to each other and chief striking a match in a gas filled room with an explosion and sirens playing as credits rolled.
In Mario Brothers, at the end of the series everyone is dead, including Mario.
Suburban Knights was originally a Bitter Sweet Ending, but the extended DVD edition turns it into this. Critic and Chester's quest for the Necronomicon is a complete failure, causing Critic to lapse even further into depression and self loathing, Malachite is still alive (albeit "trapped" in a coffee shop), Mechakara has stolen Malachite's Hand for himself, and Mati's spirit becomes bitter and vengeful over how horribly the Channel Awesome crew treated him and how no one appreciated him until after he died, which leads to the events of To Boldly Flee.
Achievement Hunter's Let's Play Grand Theft Auto V episode "The Grand Heist": After making it to a Titan and only losing Ray to a Heroic Sacrifice, the rest of the Fake AH Crew is in smooth sailing, though under attack by choppers while in the Titan. Then the Titan stalls and starts to fall, it's left wing clips a chopper and explodes, killing everyone so close to the finish line.
Subverted in A New Planet & Antimatter!. Eugene accidentally breaks a jar of antimatter, which kills Matt, sending him to heaven. St. Peter implies that Matt will shortly go to Hell, because he was never nice to Hugo and was always telling his audience to keep it sexual. But then, Matt tells St. Peter that he was just about to get 1500 subscribers, so St. Peter lets him return to Earth.
THE GREATEST EVAR! ends with Hugo getting mad at Matt for locking him up, and attacking him. Then, he faces the audience, and says, "Hugo's show now."
Anonymous ends with Anonymous taking over Matt's video.
Eggman vs. Wily: After being infected by the Robenenza Virus, Metal Sonic becomes Metal Overlord and goes on a Robenenza Virus-fueled rampage and kills all the combatants, including Eggman and Wily; and most likely, the world is doomed.
Shao Khan vs M. Bison. In a case of the worse guy wins, Shao Khan eats Bison's soul, giving him the godly Psycho Powers combined with his previous skills in sorcery. If Shao Khan wasn't dangerous before, now he's virtually immortal and twice as powerful.
Godzilla vs Gamera: Gamera gives it his all, and even loses his life, to try and halt Godzilla's rampage. He fails, and it seems unlikely that anything else can stop him.
Tigerzord Vs Gundam Epyon: Even though Zechs defeats Tommy Oliver the White Ranger, his girlfriend Noin is now dead, leaving him to cry over her demise amongst the remains of her Gundam, while Zordon mourns the loss of the White Ranger.
Ryu Vs Scorpion: In a case of The Bad Guy Wins, Ryu gets trapped in hell and gets incinerated by Scorpion.
Hulk Vs Doomsday: In another case of The Bad Guy Winsnote and also the first time in the series where a full-blown villain kills the hero, since Godzilla and Scorpion tend to be Anti Heroes, Doomsday stabs the Hulk repeatedly with his poisoned claws before ripping his head off, after which the monster is free to continue his rampage with nothing else to stop him.
Entry #25: The video consists of a recording of a news channel reporting a fire that has burned a building down. It doesn't really hit home until the end, where Jay tells us why the report is worth anything: "That was my apartment."
Entry #80: Tim is left all alone after Jay is shot by Alex and taken by the Operator, and he fails to rescue Jay as well as catch Hoody. At the very end, he grimly admits that he has no idea of what to do next.
Episode 42: Cecil is unable to free Fey, who turns out to be a computer program and remains trapped at WZZZ reciting numbers for a Numbers Station in monotone against her will, possibly forever.
Episode 46: Tamika Flynn and her army attempt to rally Night Vale to join them in overthrowing Strexcorp, only to fail and be arrested. The episode ends with Cecil's barricaded-shut recording booth being infiltrated by Lauren and another StrexCorp employee (heavily implied to be Kevin, Cecil's Desert Bluffs counterpart), cutting off halfway through the sounds of a struggle.
Episode 64: Early in the episode, Cecil talks happily about the watercolor painting he made of Carlos. When the Glow Cloud rampages through Night Vale, part of Cecil's studio is damaged and the painting is destroyed. Cecil tries to play it off as no big deal, but he's obviously very upset, and he sounds legitimately depressed for the last few minutes of the episode.
The fourth installment ends with Red Guy dead and Yellow Guy and Duck Guy still trapped in the deteriorating digital world.
The fifth installment's ending may be the most depressing one yet. Duck Guy gets grinded into canned food (alive!) and served as lunch for the Yellow Guy. The latter is then force fed every can (unaware that he had just eaten his own friend because he was drugged by the teachers), and ends up sitting in the dark kitchen, completely alone. Afterwards, the mysterious caller (who had been trying to call the two throughout the episode) is revealed to be the absent Red Guy, who had been calling from a phone booth outside. The episode ends with Red Guy, dressed in a trenchcoat and carrying a suitcase, walking away from the phone booth in the rain. It's implied that he was the one who called Duck Guy and Yellow Guy earlier in the episode. Judging by the depressing rainstorm, the somewhat melancholic jazz music, and the fact that he has a suitcase, he's certainly not happy with the results.
The sixth and final installment ends with the palette swapped puppets sitting around the table again as the Notebook starts to sing. Nothing has apparently changed, and whether the puppets will be able to escape the endless cycle of torment remains ambiguous.
The mid-season finale of Volume 3, "Fall", ends with Yang winning her fight against Mercury only to wind up being arrested on live television after (what seemed to be) an unprovoked assault against him. Ruby, Weiss and Blake can only watch on in mortified silence and dibelief as the crowd express their disgust, and the Grimm turn their attention towards Vale. It gets worse from there.
Volume 3 itself ends with Beacon being overrun by the Grimm, Pyrrha and Penny being killed, Yang being maimed, Team RWBY being traumatised and split up, and much of the world being gripped by paranoia and uncertainty. The villains' plans have largely gone off without a hitch with the exception of Torchwick's death and Ruby's latent powers being revealed.