Least Favorite Region
It's sort of a toss-up between Kanto, Kalos, and Sinnoh.
Kanto has been overdone by now and lost its luster, especially since they dialed back the creep factor of Lavender Town after R/B/Y. It's a fine region on its own, but they kind of ran it into the ground with remakes, overexposure, and pandering.
Kalos, I actually like the region for the most part. I like the aesthetics, the Pok?mon introduced (such as favorites like Malamar and Gourgeist), I liked the introduction of trainer customization, I liked how much easier it was to IV breed, I liked Lysandre, and I loved Super Trainining for making EV Training fast and easy. What really hampers it is how easy X & Y are compared to the games that came before it. The Elite Four don't even boost their levels for rematches. I enjoy the journey and then there's just nothing to do afterward except breed things for other playthroughs of other games.
Sinnoh isn't
that bad, but it's probably the least memorable region for me. Additionally, I don't know if it's just my Platinum copy but it seems like saving takes longer than it did in R/S/E/LG/FR or in HG/SS. The journal that pops up whenever you start the game is kind of annoying. I also really dislike that a portion of the game is locked off to you unless you trade with other people and have a complete Pok?dex. Oh, and the requirements to get Spiritomb.
It's probably an answer that could change from day to day for me, but right now I'd say
Sinnoh is my least favorite. A shame too, love all three of the starters and I liked that it was a colder region. It just does the least for me.
Least Favorite Generation
It kind of has to be
Generation 1 at this point. The series has advanced too much by now (physical/special split, shinies, wi-fi, etc.) for it to be anything else. I started with Red and Blue back when they first came to the US, but they're archaic now and hold no interest for me as far as revisitation goes. If I even ever felt the desire, there's always Fire Red and Leaf Green, which even offers more content like the Sevii Islands.
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As for my thoughts on the other generations:
Generation 2 snatched up all of the nostalgia of the olden days for me, as Crystal is what kept the spark of my love for the series alive when I took a break from the series from Generation 3 until HeartGold and SoulSilver came out and I got back into the series. It should, technically, suffer from being too archaic at this point as well, but I haven't felt the need to play the original versions in years so they live on in my memory as good.
Generation 3 added a bunch of great Pok?mon and had some fun mechanics. I had initially skipped out on them due to peer pressure and coming to that age where you want to leave childish things behind, but I went back and played them years later and they're enjoyable.
Generation 4 would have been a contender for worst if it was just the Sinnoh games, but HeartGold and SoulSilver were also part of this generation and they're some of my favorite games in the series.
Generation 5 is one of my favorites. Unlike most other people apparently, I was fine with them starting fresh with an entirely new Pok?dex. It was my first new experience with the series since I returned after my years long break with HeartGold and SoulSilver, so I was totally open to the idea. I love the Pok?mon they introduced in Generation 5, the story was fine, they added the Pok?mon World Tournament in B2/w2, and you can just transfer up the older Pok?mon if you so desire. It was also the first set of Pok?mon games where I could utilize the wi-fi function and I loved it.
Generation 6, like Generation 4, is saved by the remakes Omega Ruby and Alpha Sapphire carrying the weight for X & Y, though to a lesser degree because I find X & Y has a few more positives than D/P/Pt did despite being too easy.
Generation 7 initially left me very disinterested because it, again, was too easy with the intiial Sun and Moon. Despite having a weaker story, I came to appreciate Generation 7 far more with Ultra Sun and Ultra Moon. I now really love the Festival Plaza and how much customization you have with the colors at the dye shops (although I wish you could host more facilities at once), I really like how fast it is to EV Train with the Power Items in combination with Pok?rus. It went from a contender for worst generation to actually being pretty good.
There's something to be said for the part of the team that handles the remakes/second versions. HG/SS, B2/W2, OR/AS, US/UM, they're some of the best experiences as far as I'm concerned.