The Nuzlocke Challenge can already be a tough challenge for many, and certain games can make this way harder. The mainline Pokémon games have changed a lot over the years, with each generation adding new quality-of-life changes, new mechanics and, usually, new Pokémon or even types. This means some games are much easier to run through in a Nuzlocke, while others may stop a party dead before even getting past the first Gym Leader.
A Nuzlocke Run is when you play a Pokémon game with specific rules attached. The three most common Nuzlocke rules are: only the first wild Pokémon encountered in an area may be caught, with no retries, all Pokémon obtained must be nicknamed and fainted Pokémon are considered dead and must be placed in a box never to be used again. This means lots of training, knowing the game, and being smart about battles and team compositions, and which game being played can make things easier or harder.
Pokémon X & Y is the Best Game for Nuzlocke Beginners
The sixth generation of Pokémon games are considered the easiest in the mainline series as the jump to 3D is where the quality-of-life changes began to streamline most of the challenge. Two of the biggest challenges with Nuzlocke runs are major battles and the Pokémon available. In Pokémon X & Y, leveling and battle progression have a much more gradual curve than most games, meaning it's easy to raise a team or replace a fainted Pokémon. A few battles pose a challenge, but these can be easily prepared for by knowing where they are or just spending extra time training. There were also over 700 Pokémon available by this point in the series, so while X & Y didn't add many to the roster, there are plenty available in-game.
Another huge boon that makes these games the best Nuzlocke choice is how easy some major battles are. Many Gym Leaders don't have a full team. Even the Elite Four, the real challenge of a Nuzlocke run, don't have full parties. This makes getting through these challenges easier. There is also one extremely helpful change: the EXP. Share, which was boosted in this generation. The item allows all Pokémon in the party to get large amounts of EXP even if they didn't fight, and more so than before. This means less time grinding levels. X & Y also added Mega Evolutions for the first time, although not all Nuzlocke players use them. All of this combined makes it one of the easiest Pokémon games to run a Nuzlocke.
The Hardest Nuzlocke Challenge is Pokémon Sun & Moon (or Ultra Sun & Ultra Moon)
Pokémon Sun & Moon and their upgraded counterparts are considered the most challenging games to Nuzlocke. This is mainly because of the use of Totems rather than the traditional Gyms. Getting through the initial trials isn't too bad but fighting the Totem Pokémon themselves is another story. Many major battles in these games can be pretty difficult as the AI is smart and the team compositions are well structured. There are plenty of fights where players will lose team members. Training up is also more difficult as there aren't many places to battle trainers and each new area has a fairly high level jump, making EXP. Share a huge necessity.
Like X & Y, there are a large number of Pokémon available to construct a team, and plenty of different areas around the islands to boost the number of them in a trainer's possession. However, they may be tough to snag because of the curve. Another reason Sun & Moon are more of a hurdle is because of the story. It has the most cutscenes of any Pokémon game, and if a team is wiping often, it means sitting through them over and over again. This is a different type of slog, but a tedious one. Even with a lot of the quality-of-life changes brought in, this is a tough game to run through with random Pokémon and requires a lot of knowledge on what to expect and Pokémon themselves. Definitely don't attempt this if you don't have experience with these titles unless you aren't looking to make it all the way through.