It could be an original character created just for the fanfiction. Maybe a powerful ninja from a forgotten clan who has a vendetta against Konoha and targets Naruto, Sasuke and Sakura specifically.
In some fanfictions, there could be a group of rogue ninjas who form an alliance during the war. They have no loyalty to any particular side and are only interested in causing mayhem. Sasuke and Sakura would have to deal with their unpredictable attacks and devious plans.
In some fanfictions, there could be a co - worker who has a secret crush on Sasuke or Sakura. This co - worker then tries to drive a wedge between them by spreading rumors or causing misunderstandings in the office environment.
There could be an outside force, like a neighboring village that wants to keep Naruto and Sasuke away from their own village. They might be afraid of the potential power and influence Naruto and Sasuke could bring back if they return. So, this neighboring village sends their best ninjas to hunt down Naruto and Sasuke during their banishment, making them the main antagonists in the fanfiction.
There could be a mysterious organization that has been hidden for a long time. They emerge when Sasuke and Sakura start their journey. This organization wants to use Sasuke's power and Sakura's medical knowledge for their own evil purposes. They set up traps and send assassins to target the duo throughout their journey.
Often, it could be a group of rival students from another college who are jealous of Naruto and Sakura's skills or achievements. They might try to sabotage their projects or disrupt their college events.
It could be the Akatsuki members. Since they are often the main villains in the Naruto universe, they might also play that role in this fanfiction. They could be trying to stop Naruto from using his control over Sakura to achieve something that would be a threat to their plans.
Perhaps there is an ancient evil entity that feeds on the hatred between werewolves and vampires. It doesn't want Sasuke and Sakura to succeed in bringing peace. So it uses its dark magic to create misunderstandings and conflicts between the two, trying to keep them at odds and prevent any chance of unity.
In this kind of fanfiction, the Fallen Angels could be main antagonists. They might see Naruto and Sasuke as threats to their plans in the DxD world.
In some fanfictions, a new character could be created as the main antagonist. This character might be jealous of Naruto and female Sasuke's growing relationship and power. They try to create rifts between them and stop them from achieving their goals.
Often, Orochimaru can still be a main antagonist in these fanfictions. He might have some new, devious plan related to the Chunin Exams, like using the chaos of the exams to steal some powerful jutsu or secrets from the village.