The final villain of One Piece is the inevitable march of time.
One Piece is a long-running series, long enough that some readers weren't born yet when it started. There's memes about how long it's been going and how it gets better after the 2586th episode. It's easy to see a series that's been going on for so long as a normal part of life, a constant, and to joke about how long it is or how it's never going to end.
But one day it will reach a conclusion. Not long after that day, fans will be hit with the cold, hard reality that they'll no longer get their weekly chapter. Which was fine when it was on break for a week, because you knew it'd come back the week after (or in a couple weeks sometimes during holiday breaks). But never having another chapter again? No longer seeing the great adventures, the glorious triumphs and struggles and the silly antics of the rubber pirate crew ever again? Something that was a normal part of your week for years, maybe even decades, has gone. Something you might not remember what it's like to live without is now something you'll never live with again, and you'll have to figure out how to fill that void.
Maybe you'll fill it by finding another manga to read. Or a webcomic or some other weekly serial. One Piece certainly isn't the only one out there, and maybe you'll find one you like even more. But then you'll have to deal with the aftermath of your replacement series ending someday too. Maybe you'll reread the series from start to finish. But in doing that, you'll constantly be aware of how it's over, and that you'll never get another chapter.
Whether you think the final villain is Blackbeard, the World Government, or someone else, it's undeniable that the passing of time dwarfs every villain and hero in One Piece in scale. Unlike them, who will either be defeated or have their body give out to age eventually, time isn't temporary, in-universe or out of it. We were born of the void and the void will eventually consume all of us again.