A powerful demon lord from the DMC world would be a great antagonist. This demon lord could see Toothless as a threat or a tool to use for his evil plans. He might try to corrupt Toothless or use his power to gain an edge over the DMC heroes.
A rogue dragon from Toothless' world that has been corrupted by the dark energy of the DMC world could be the antagonist. This dragon could be jealous of Toothless' connection with the DMC heroes and seek to destroy them all. It would be a formidable foe, having the strength and abilities of a dragon combined with the dark influence of the DMC world.
One idea could be that Toothless somehow gets transported to the DMC universe. Maybe he forms an unlikely bond with Dante. Since Toothless is a powerful and intelligent dragon, he could assist Dante in fighting demons, using his speed and fire - breathing abilities in unique ways.
If it's a crossover with Alice in Wonderland, the Queen of Hearts could be the main antagonist. The Queen might see Tinkerbell as an intruder and try to behead her. Tinkerbell would have to use her wits and magic to survive in the crazy world ruled by the Queen of Hearts.
A powerful demon from another dimension could be the main antagonist. This demon could be attracted to the power that Sinbad wields in the Magi world and wants to steal it for himself. He could start causing chaos in both the world Sinbad is from and the world he's been transported to in the crossover.
A new character could be introduced as the main antagonist. For example, a being from another dimension who has been observing both Sonic's and Megaman's worlds. This being realizes that by combining the chaos energy from Sonic's world and the advanced robotics technology from Megaman's world, it can create a new, all - powerful empire. So it starts to manipulate events in both worlds to bring about this combination, while Sonic and Megaman have to stop it.
Dr. Eggman and Dr. Wily could team up. Dr. Eggman has his mechanical creations and knowledge of Sonic's world, while Dr. Wily is an expert in creating powerful robots in Mega Man's world. Together, they could be a formidable force against Sonic and Mega Man.
Thanos could be an interesting antagonist in a crossover. Imagine Dr Fate having to use his magic to try and stop Thanos from getting all the Infinity Stones. Thanos' brute force and determination would be a great contrast to Dr Fate's magical finesse.
An alien entity that has been dormant beneath Smallville for centuries could awaken. This entity could view Chloe and Clark as threats to its plans of taking over the town and the world. It could use its advanced powers to manipulate the townspeople and turn them against Chloe and Clark, making it a formidable foe.
Perhaps an ancient evil that has been sealed away in the empire for centuries but is released due to the chaos of the crossover. This entity could be more powerful than any foe the Naruto characters have faced before, forcing them to find new ways to fight.
A group of rogue shinobi and some of Daria's school bullies could team up. The shinobi would give the bullies some ninja powers, and together they would cause trouble in both worlds. This group would be difficult to deal with as they combine the physical strength of the shinobi with the local knowledge of the bullies.
It could be a lemon - loving pirate who has a grudge against Luffy for some reason. Maybe Luffy accidentally destroyed his precious lemon grove on an island. So this pirate, with his crew of lemon - themed fighters, constantly tries to sabotage Luffy's adventures and steal his treasures.