Great question. It's so hard to decide, because you can approach it so many different ways.
I would say my favourite protagonists are a split-tie between the gen 2 protagonists, and the gen 5 protagonists (covering both BW and B2W2).
(I'll always wish we got to see Gold/Kris in future titles. We've seen Red return in HGSS, B2W2 and gen 7; but he was defeated by Gold/Kris at the end of Gen 2/4. How come they don't get to live on as legends?)
I think their designs are pretty peak overall; specifically, I like Kris/Crystal's design far more than Lyra's. Gen 4 Gold was a modernized version of his Gen 2 clothing, which ultimately just fit with the aesthetic of "protagonist trainer" at that point in time.
Lyra has a farm-girl outfit. Which is cute, for sure, but just too specific and stylised. I would've much preferred if they just updated Kris and her outfit; I'll never understand why they decided to split the two characters.
Moving onto gen 5, same deal - their designs are excellent, in both the originals and the sequels. The only complaint I have is for the atrocious canon names of Hilbert and Hilda. "Black" and "White" were right there, and just... wow. Truly awful. But their outfits are awesome. As slightly older protagonists, they just... don't look as childish as the likes of Gen 7 and 9, and both provided the long-awaited return to a good ol' baseball cap, like Red and Gold wore. I'm kinda sad we never got a big boss battle against them in B2W2.
The designs for Nate and Rosa are also excellent. a little bit stylized, in that they seem to be wearing a sporty-under-layer (which I'd thought was a wetsuit, and that can't make sense because they literally live in a landlocked city, Aspertia). I like how they share similar colour schemes to Hilbert and Hilda, but their crazy hair differentiates them substantially.
A lovely detail is that their hair (which is a significant feature of their design) matches their mother's.
The mother has a bun which matches Rosa's two, and she also has locks dropping to the side which match Nate's hair. Just a nice little detail.