Perhaps Brainiac. He is always seeking knowledge and power. In a story where the Justice League meets Batgirl, he might target Gotham as a source of new information or technology. Batgirl, with her knowledge of the city, could help the League stop him from stealing Gotham's secrets.
It could be the Joker. Since he's one of Batgirl's main foes in Gotham, his chaotic nature would pose a great threat to the Justice League as well when they enter Gotham's affairs.
It could be Darkseid. He's a powerful and well - known villain in the DC universe. His goal of universal domination would put him in direct conflict with the Justice League and Batman's determination to protect Gotham and the world.
The League of Shadows could be a great antagonist. They might see Young Justice as a threat to their plans in the world and Batgirl as an obstacle in Gotham. They could try to manipulate situations to make Young Justice and Batgirl turn against each other while they carry out their own devious plans, like releasing a dangerous virus in a major city.
The Riddler could be a great antagonist. He might have a grand scheme that not only affects Gotham but also has implications for the Justice League's interests. His riddles could stump both Robin and the League members, forcing them to work together to decipher his plans.
It could be a new villain who has a vendetta against both Batman's family (including Batmom) and the Justice League. Maybe a powerful criminal mastermind who has studied both sides and found their weaknesses.
Well, it might involve Batgirl initially being a bit of an outsider among the Justice League. But then she proves her worth by taking on a powerful villain that the League has trouble with. For example, she could use her agility and stealth to infiltrate the villain's lair and gather crucial intel that the League needs to make their big move.
The Court of Owls would be a great main villain. They are a powerful and secretive organization in Gotham. Their connection to Gotham's history and their shadowy nature could pose a huge threat to both Young Justice and Batgirl. They might be after some meta - human power or trying to take over Gotham in a new way.
The Reverse - Flash could be a great main villain. He has a long - standing feud with Barry Allen and his presence would force Barry to team up with the Justice League. The Reverse - Flash's ability to manipulate time in his own way could pose a huge threat not just to Barry but also to the entire Justice League.
A tech - genius named Techno - Tyrant. He could be a former game developer who turned evil after his creations were rejected. He uses his knowledge of gaming mechanics and virtual reality to create dangerous traps for the Justice League.
Lex Luthor could be a great main antagonist. He might see Izuku as a threat to his plans, especially if Izuku's unique abilities and sense of justice start to disrupt Luthor's schemes in the combined universe. Luthor could try to manipulate events to turn the Justice League against Izuku or find a way to steal Izuku's power for himself.
Obviously, Batman and the members of the Justice League are the main characters. Batman is the Dark Knight, known for his intelligence and combat skills. And then there's Superman, the Man of Steel with super strength and other powers. There's also Wonder Woman, a powerful Amazon warrior.