Rocky and Bullwinkle.
Paranoia Agent probably gets in the top 50, at least.
(Although including anime in the running might be cheating, a bit. Even if you exclude the ones showcasing parody/referential elements.)
No love for the Venture Brothers? C’mon, that is one stellar series
That was going to be my nomination, alongside South Park.
One more vote for Rocky and Bullwinkle. And get the DVDs, it’s amazing how much a 10 year-old missed the first time around that a 60-something year old can catch with a re-watch.
Animaniacs, especially the songs.
Probably an Unpopular Opinion, but Cow And Chicken was a HOOT. The Red Guy has to be one of the most brilliant characters ever. And I’m probably the only person on the planet who thinks Cow’s voice was funny. So sue me.
Animaniacs was Looney Toons with a turbocharger. For an entire decade it defined creative, fun, funny, irreverent, endlessly entertaining, and at times sentimental (some of the Rita and Runt sketches moved me to tears, I kid you not) animation. The only part I thought was a little weak was the Hiphippos, and even they had their moments. One segment, Pinky and the Brain, got so popular it spun off into its own show. That’s how huge this was.
Freakazoid broke all the rules, laughed in the face of convention, and didn’t once try to be even remotely coherent. It was amazing. It was clear everyone involved just wanted to have fun and, more importantly, let the audience just want to have fun. It was like the polar opposite of the eternally formulaic and dreary Taz-Mania. A shame it only lasted two seasons.
And once again, Duckman. Tragically ahead of its time and NEVER, EVER got its due. The best thing I can say about it is that it knew exactly where the line was when it came to edginess and never forgot the importance of a good story. Any show that puts a loud, dumb, obnoxious, tedious jerk like Eric Duckman front and center and not only makes him genuinely funny but sometimes sympathetic is doing something right.
Duckman was a great show and probably the one that convinced me that animation could be an adult medium as well as a kids one. A great show with spot-on casting of Jason Alexander as the titular character.
Given the popularity of shows like Archer and Bob’s Burgers now, I’d love to see someone reboot Duckman as well.
Changed the way I watch cartoons as an adult.
Simpsons, and South Park were and are contenders for this thread title. But while I love Venture Brothers (to death!), they aren’t in contention. Once you make the decision to set your world in parody of a particular genre (in this case 1970s arch-villain vs superspy stories) then the gags are just there for the picking. You don’t need to be creative so much as send it up. YMMV
I rate Adventure Time very highly (I rate Steven Universe higher) but I have to ask, since the OP says "They’re constantly coming up with characters, settings, creatures, the likes of which I’ve never seen before " - has the OP ever roleplayed?
The Venture Bros is quite a deep show though - it’s less about sending up the 1970s/1980s Saturday Morning Adventure Cartoon genre as it is about exploring the themes of failure and not living up to one’s potential.
Bojack Horseman is another show in the same vein - you’ll spend the first episode or two laughing at the wacky self-centred talking horse and then the show gets dark and also very deep.
Comedy Central (I think…now I’m second guessing myself) had an animated series for a while, and I’ll be damned if I can remember the name of it, but it was really funny and pretty creative.
It starred a regular guy, but he was living in a world with monsters and zombies and stuff. His roommate was a zombie, his girlfriend was the daughter of the devil and there were all sorts of weird monsters about. I think his job was a therapist? It was called something like “America, USA” or “Weird America” “Modern America?” Ugh. Can anyone help?
Ugly Americans.
Yes! Thank you!
I knew I was close on the title. What a good show that was.
THIS. Metalocalypse took a concept that seemed rather silly on the surface – a self-absorbed metal band unaware of their godlike powers – and made an amazing story out of it. (And who would have thought that the lawyer/manager/CFO would turn out to be such a badass? 
)
Venture Brothers is similar to me…it started out as a playful parody of classic adventure cartoons, but the underlying story is quite serious.
This one never fails to disappoint…even the plotless episodes (mostly done by guest animators, I think) are awesome to watch. Long before the show’s backstory was made official, many viewers already had a hint that something deeper was going on because of all the little bits of an apparent civilization left lying around. And the transformation of the Ice King from terrible villain to sympathetic character was moving.
Steven Universe also belongs in this category. That show has tackled some really serious topics, and also features a nice mix of plot-heavy episodes with fun or thought-provoking pieces. And the art is gorgeous, too – especially the outer space backgrounds.
…dunno about “…of all time” but Archer has gotta be up there.
Regular Show definitely deserves some mention in this conversation. The writing and character development were great. In the earlier seasons it had a tendency to go a little too crazy/trippy, but the extended story arcs were great.
I’m glad someone mentioned Cow and Chicken and Duckman.
We have a five-year old granddaughter, so I’m thinking of the shows she would watch. We’ve been really impressed with Zack and Quack, where their entire world is set within a pop-up book. Every scene change is a pull of a tab that turns a page. It’s really cute (and kind of trippy).
Yeah, but so did Get Smart, Married With Children, and… actually most comedy shows.
Not necessarily. And we’re talking about animated shows, so a deconstruction of the Saturday Morning Adventurers and Supervillains genre definitely qualifies as creative IMHO.