When the Wind Blows charts the slow death from nuclear fallout of an elderly couple after a nuclear bomb goes off in England.
Originally a graphic novel (and also a Radio play). And of course their deaths are the Anvilicious point of the story, meant to show up the absurdity of the British Government's civil defence plans.
Intentionally done in the pilot episode of Ĉon Flux (actually drawn out into six two-minute shorts), in which the main character's guns-blazing assassination mission fails when she steps on a nail and falls to her death, her body and even her apartment being destroyed by her superiors, her assassination target dead by other means, and her entire shooting spree of a mission being futile.
The second season, dealing with the question "How do we do a sequel when the protagonist is dead?", turns this trope up to 11 by having her die (pointlessly) in every episode.
The continuity-less series kept the protagonist alive (mostly), but episodes often end with the trans-humanist Big Bad being right and when the protagonist is successful, she's successful in unwittingly destroying humanity.
In the movie version of The Plague Dogs, the movie ends with the two dogs swimming out to sea and drowning after their fox friend had just sacrificed himself to give them time to escape; this wasn't how it was in the book—see above. The real kicker is that many people prefer the movie ending, that's how bad the Deus ex Machina was in the novel.
Also the OJ Simpson episode. After building up that they shouldn't just assume that OJ was really guilty, at the very end he stabs a couple people to death and runs off, ending with Peter saying "Oh, I guess he did do it then."
Happens AGAIN in the banned abortion-based episode, which revolves around Lois struggling to decide wether to keep a baby she is the surrogate mother for after the parents die in a car crash. At the end, she gives the family a long speech about love and family, only for Peter to say "we had the abortion" a second before the credits.
Brian's estranged son Dylan gets him script writer job at the show he's starring in, and Brian soon gets fired because he keeps trying to inject this kind of endings and plots into the show. Problem is, this is a Disney Channel tween sitcom.
Although he then gets shot by Bender's death ray to get "fast-fossilized".
Which is still better than the original ending, as this time the dog got to see Fry again, which in the original timeline he did not, and died a quick, mostly painless death, which in the original timeline was slow and cruel.
In the Looney Tunes cartoon "8 Ball Bunny", Bugs Bunny comes across a penguin. After swearing he would help the penguin get home (after regretting making him cry), he finds out that penguins come from the South Pole ("South Pole?! Ooh, I'm dyin'!"). He tries to help the penguin to the Antarctic, going through hell and high water to do so, only to find out when he finally gets there that this was a domesticated performing penguin who lived in Hoboken ("Hoboken?! Ooh, I'm dyin' again!"), and he just dragged him several thousand miles for nothing. It would be just a regular "Shaggy Dog" Story, except that the usually calm, impossible to beat Bugs suffers a mental breakdown because of it.
This trope is cruelly used in the Private Snafu short "The Chow Hound", in which a bull gives his life to be turned into meat to be delivered to Snafu to feed him in order to fight the enemy. Unfortunately, Snafu has eaten so much already by the time the package arrives that he throws out the bull meat, such to the chagrin of the Bull's ghost.
Another memorable one is that one of Cyberton's satellites comes to Earth looking for the Maximals. The group quickly puts together a beacon in hopes of contacting it, but the Predecons get wind of their actions and a fight ensures. Just when it looks like the Maximals will get the signal out, Megatron manages to get in a last minute shot and destroy the beacon, vowing he won't let them leave until he wins the ongoing battle between the two groups.
The South Park episode "Stanley's Cup", a Mighty Ducks parody which ends with a pee-wee ice hockey team being beaten bloody by a professional team, and their teammate dying of cancer. "Woodland Critter Christmas" also qualifies, to a lesser degree: the episode consists of a story written by Cartman in class for the sole purpose of saying Kyle died of AIDS at the end.
And then those woodland critters turn out to be the most evil monsters ever created by anyone's imagination.
There was also the massively drawn-out prank played on the boys by two amusement park employees to make them think that a whale was sentient, leading them to kidnap the whale and eventually condemn it to death by blasting it to the moon. Oh, and one of the two employees gets shot to death by the Animal Liberation Front.
"Whoopie-Ti-Yi-Yo, Farewell, Magellan. You almost made it, it's really not fair. Whoopie-Ti-Yi-Yo, oh Ghost of Magellan, the East Indies Islands were right over there".
An episode of Jimmy Two-Shoes had Jimmy trying to keep Lucius from destroying "the last non-miserable spot in all of Miseryville." In the end, he manages, and Lucius calls to cease-fire... but Samy and Molotov mishear it and think he ordered them to fire.
Toph Beifong's story ends up being this. After her adventures with the original Team Avatar, she grows up and becomes the police chief for New Republic City, where she created the metal bending squad. She also has two daughters by two different men. Not liking that she was pampered as a child, Toph decides to let her daughters take care of themselves when they reached the same age she did when she ran away from home to fight in the earth bending arena. Both daughters grow up with abandonment issues as a result, but Toph doesn't notice because she is Married to the Job. Lin tries to follow in her mother's footsteps by going into law enforcement too, but becomes cold and antisocial as a result. Suyin really follows her mother's footsteps by rebelling against her and getting involved with petty crimes, until she is finally caught by her older sister. Toph Beifong, after dedicating her life to cleaning up the streets, had to face the fact that one of her own daughters is now a criminal. She couldn't face it, so she destroyed the evidence against Suyin and sent her away to live with her grandparents. And after years of guilt for the coverup, she resigned as the chief of police while during the prime of her career. She leaves civilization behind and spends the reminder of her elder years wandering the planet by herself.
In the flashback to the first Avatar, Wan, his story ends with him lamenting that despite his best efforts and the changes he'd made, war and misery never really left the planet. Raava, the spirit who fused with Wan to become the Avatar, says that she will be with him through all his lifetimes to accomplish this goal. We're 10,000 years in and this flashback occured during the current avatar's mental breakdown. Not to mention one of Wan's first acts was to seal the spirit portals, something that Korra undos at the end of the season.
Played straight, then subverted in Gravity Falls. In "Into the Bunker", the twins find a laptop that may provide more insights into the secrets of Gravity Falls, as well as the author of the journals. In "Sock Opera", the laptop ends up smashed by Bill Cipher. But in "Society of the Blind Eye," the broken remains of the laptop reveals an important clue: Old Man McGucket, who is later revealed to have worked with the author, only to have caused a disaster so terrible, he erased his own memories. It is indicated that he is slowly regaining his memories, though, and maybe able to find the author.
And then Grunkle Stan reactivates the portal and brings back his long lost brother, who is also author of the journals. This turn of events not only renders all previous attempts to find the author completely pointless, but also proves that they wouldn't be able to find him anyway, since he was in the other dimension and nobody knew that he disappeared because his twin took his place.
The Cipher Wheel, hinted at throughout the series, ends up being pointless because Stanley refuses to take Stanford's hand and complete the wheel because he was never thanked for bringing the latter back from the other dimension. The hesitation allows Bill to turn most of the Cipher Wheel's participants into tapestries, forcing Dipper, Mabel, Stanford and Stanley to find an alternative way to defeat him.
In The Venture Bros. episode "All This and Gargantua-2", The Sovereign tries to wipe out The Investors. In order to do so, he kills most of the Council of 13 so he can destroy Gargantua-2 without their interference, which he believes they are on. Unfortunately, they turn out to be powerful psychics whose actions on board were likely just mental projections, so his plot never had a chance of succeeding and probably only managed to cripple The Guild of Calamitous Intent and piss off OSI. Meanwhile, Killinger kills The Investors on mostly unrelated business, but Sovereign can't reap the benefits since he gets accidentally killed in his eagle form by Headshot.
Toonami's The Intruder II does this to its own tie-in prequel comic, as the comic had TOM 4 fend out the Intruder, yet Week 5 of the event proper has the Intruder gloat about killing TOM 4, anyway.
Rick and Morty: "Mortynight Run" has Morty rescuing an alien named Fart from a hit man and trying to take him back to his home. Right as Fart is about to get home, he reveals to Morty that once he gets there he plans to come back with an army and destroy all carbon-based life forms, and Morty kills him to prevent this, making the whole thing pointless.
"Vindicators 3: The Return of Worldender" has Rick and Morty teaming up (again) with the Vindicators, a Justice League-type superhero organization, to take down Worldender, a villain hyped up by Word of God prior to the episode airing as the most dangerous villain Rick and Morty have ever faced. Rick kills him while blacked out the night before they are to invade Worldender's fortress, and the remainder of the episode is spent trying to escape the fortress, which drunk Rick has turned into a series of death traps a la Saw.
Most of "The Rickchurian Mortydate" is a battle between the President of the United States and Rick after the latter refuses to continue doing vaguely supernatural dirty-work for the President and refuses to leave the Oval Office if he doesn't take a selfie with Morty. After the battle is over, resulting in the deaths of many Secret Service agents and two Brainwashed and Crazylittle girls, Rick discovers that Morty had long since given up on getting the selfie (even when he was still there, he insisted the selfie wasn't necessary and just wanted to leave), left and is currently in hiding with Summer and his parents. It also undoes Rick's banishment of Jerry in the season opener, as Jerry and Beth have decided to get back together and reduce Rick's influence over the household, which he concedes to.
Samurai Jack: After being defeated by Jack and reduced to a head, the robot Musical Assassin Scaramouche spends his next two episodes trying to get to Aku's citadel to inform him that Jack has lost his sword, the only weapon that can destroy Aku. He succeeds and Aku restores his body, but by the time he does Jack has already retrieved the sword, and when Aku sees that Jack has it again he blows up Scaramouche's head.