We have to make our peace with the fact that The Simpsons genuinely may never end - that it's just an institution on television at this point, like SNL. Cast members and writers may come and go, but the show (which has been on for 27 years) will continue regardless. And that means it's pretty unlikely that The Simpsons will ever get a proper series finale, at least in the near future.
Luckily, the Simpsons DID produce what would have basically been a perfect series finale back in season 11 (and to many diehard Simpsons fan, this is essentially where the show ended): Behind the Laughter, a meta-look at the history of the Simpsons as in-universe celebrities, who are aware they're on a popular comedy show and the travails of fame and fortune that go along with it. And, hell, it even (jokingly) reveals the actual location of Springfield (Northern Kentucky, in case you don't remember).
30 Rock's antepenultimate (that means 3rd to last, I checked) episode is really the summation of Liz Lemon's journey - she's desperately trying to keep TGS With Tracy Jordan on the air (and compromising the show further than she ever had before) and is juuust about to adopt some kids (thus fulfilling her "having it all" wish established early on). And this is all well and good, but it's the final moment of the episode that totally sells this as the perfect ending for Liz.
Liz rushes to the airport to greet her newly-adopted kids...who just happen to be mini, younger versions of Tracy and Jenna, her most problematic co-workers who caused her endless amounts of stress and anxiety. And when Liz hears them, respectively, talk about their lizard and pronouncing "ca-mer-ahhh", it clicks: the entire series was retroactively about getting Liz ready to raise these two kids. Every headache she put up with and every disaster she had to deal with suddenly made sense, because it was training for her as a parent. It's surprisingly sweet and perfect.
Also, Kenneth is named president of NBC, which is nice.
South Park could honestly end at any moment - if Trey Parker and Matt Stone didn't feel like doing it, it would disappear from existence in an instant. That being said, they're 19 seasons in and still innovating the formula and keeping things fresh, so the end may be a long way off (it probably helps that the production is hypercompressed by spending only 1 week per episode).
That being said, You're Getting Old could have easily worked as a series finale for the show - and it honestly seemed to be hinting (at the time) that it WAS (or at least reflected the frustrations of its creators with the limitations of the show). In the episode, Stan celebrates his 10th birthday and grows increasingly cynical about the world. Meanwhile, his parents have a series of genuine, frightfully realistic (for the characters) arguments that culminate in the realization that they really don't belong together. The whole thing is a little dour and mostly grounded, and seemed to indicate weariness on the part of the creative team behind the show.
And it would have been a pretty incredible finale - downbeat and (most importantly for South Park) totally unexpected and brutally honest about an unfortunate part of life: getting older and learning how to move on towards new experiences.
That being said, the more serialized past few seasons have been pretty exceptional, so it's a good thing this wasn't the end. I mean, PC Principal, right?
Technically, Futurama has produced somewhere around 4 series finales (The Devil's Hands Are Idle Playthings, the last section of Into the Wild Green Yonder, Overclockwise, and - the ACTUAL series finale - Meanwhile), and two of them even work pretty well as actual finales (not surprisingly, it's The Devil's Hands and Meanwhile, the two episodes that DID actually function as series finales). But the one episode that's always stuck out is The Late Philip J. Fry - which saw Fry, Bender, and Professor Farnsworth stuck traveling endlessly forward in time.
As with the best Futurama episodes, it pretty perfectly blends sci-fi concepts, philosophical musings, and Bender talking about his shiny metal ass. But more importantly, it served as a perfect summary of the Fry-Leela relationship without ever getting too maudlin or gooey about it.