Maybe Madara Uchiha. He sees the Avatar as a threat to his plans of reshaping the world. He would try to either break the seal to control the Avatar or make sure the Avatar stays sealed so it doesn't interfere with his grand scheme. His powerful abilities and cunning nature would make him a formidable adversary in this fanfiction.
It could be Orochimaru. He might have learned about the Avatar's unique power and wants to use it for his own dark experiments. So he tries to break Naruto's seal to get to the Avatar. He would be a great villain as he's always after powerful things and doesn't care about the consequences.
Well, perhaps in this fanfiction, the Avatar enters the Naruto universe and causes some sort of imbalance. Naruto, seeing the chaos it might bring, decides to seal away the Avatar. As time passes, Naruto starts to learn more about the Avatar's world and realizes that there are good things about the Avatar too. So he begins a journey to find a way to unseal the Avatar without causing more harm, all while facing enemies who want to use the situation for their own gain.
It could be Orochimaru. He has always been interested in power and Naruto's unique abilities. With Naruto sealed away, Orochimaru might see it as a chance to steal whatever power Naruto had or use his absence to further his own evil plans in the ninja world.
A corrupt leader from a political - based crossover world might be the main antagonist. He views Naruto as a threat to his power, especially with the mystery of his seal. So, he tries to either keep Naruto sealed away permanently or use the situation to gain more control over his own people by creating fear around Naruto's presence in their world.
Another option is that a new character introduced in the crossover could be the main character. For instance, in a Naruto - Fullmetal Alchemist crossover, an alchemist from the FMA world could stumble upon Naruto's sealed state and make it their mission to free him, while also getting involved in the politics and power struggles of the Naruto world.
The main antagonist could be a new character created specifically for the fanfiction. This character might be from a long - lost clan that has a grudge against the Uzumaki clan, of which Naruto is a part. Since Naruto is the last of the Uzumaki in the village, sealing him away would be their first step in getting revenge on the clan, and they would do everything in their power to keep him sealed.
One possible reason could be that his godlike powers were seen as a threat. The village elders or some powerful forces might have feared that Naruto, with his immense strength, could lose control and cause destruction. So, they decided to seal him away to protect the village and the world at large.
There's also the possibility that it was an accident. Some kind of jutsu gone wrong during the sealing process. The person performing the sealing might have been inexperienced or there could have been some unforeseen interference that led to Naruto being sealed away instead of the Nine - Tails being properly sealed within him.
It could be Orochimaru. He's always been interested in power and with Naruto having the Asura power in this fanfic, Orochimaru might see it as a great opportunity to steal that power for himself and use it to create an even more powerful battle avatar.
It could be a powerful dark wizard in the Fairy Tail world who mistakes Naruto for a threat. Maybe they sense his chakra and think it's some kind of dangerous magic they need to contain.
The story could also focus on the efforts to unseal Naruto. His friends and the characters from the crossover world could embark on a dangerous journey to find the key or the magic to break the seal. In a Naruto - Harry Potter crossover, Hermione might use her vast knowledge of magic to research a way to free Naruto from the seal.