Perhaps an interdimensional villain. This villain could be causing disruptions in both The Flash's and Supergirl's dimensions, forcing them to meet and join forces to stop it. The villain could have powers that are a challenge for both of their unique abilities.
Another option is a new super - powered being created by an experiment gone wrong. This being could have a grudge against heroes in general and target The Flash and Supergirl specifically. It would be interesting to see how they deal with an enemy that has powers they haven't encountered before.
Lex Luthor could be a great main antagonist. He could be jealous of their combined power and see them as a threat to his plans of world domination. He might create some high - tech weapons specifically designed to counter their abilities.
A powerful alien warlord could be the main villain. This warlord might have his eyes on Earth because of its resources or strategic location. Supergirl and Wonder Woman would have to use their unique powers and teamwork to defeat him. He could have an army of minions and advanced technology that makes him a formidable foe. They would need to figure out his weaknesses and come up with a plan to stop his invasion.
Lex Luthor would be a great choice. He could be causing trouble in Gotham as well as Metropolis. His intelligence and resources would pose a significant threat to both Supergirl and Batman. He might be trying to manipulate events to make the two heroes fight each other so he can carry out his evil plans.
Reverse - Flash could be really interesting. He could manipulate time in ways that not only affect Flash but also Supergirl. For example, he could go back in time and prevent Supergirl from arriving on Earth, which would change the whole timeline. Flash would then have to convince her to come to Earth again while also dealing with Reverse - Flash.
Lex Luthor could be a great villain. He might be jealous of Supergirl's powers and see Flash as an obstacle in his plan to defeat her. He could use his scientific knowledge to create some sort of weapon that targets both speedsters and Kryptonians.
Supergirl would be really interesting. Her alien origin and her super strength, along with her ability to fly, would make her stand out. She could bring a new dynamic to Team Flash with her different set of powers and her more idealistic view of heroism, which might contrast with some of the more street - level concerns of Team Flash.
In a 'Supergirl meets the Flash fanfiction', they might team up to fight a powerful common enemy. For example, a super - villain who can manipulate time and space, and only their combined powers can stop him.
Lex Luthor from Supergirl's world could be the villain. He could somehow find a way to travel to the wizarding world and team up with some dark wizards. He wants to use magic to enhance his power and take over both worlds. Supergirl and Harry Potter would have to stop his evil plans.
In a 'Team Flash meets Supergirl' fanfiction, there could be an epic team - up. The Flash might use his super speed to save Supergirl from a kryptonite - powered trap. Then they could join forces to fight a common enemy like Lex Luthor or an alien invasion. The scientific minds in Team Flash could also help Supergirl understand some new aspects of her powers.
The Reverse Flash could also be a main villain in this crossover. He travels to the Smallville universe to cause trouble. He might target Clark, thinking that by eliminating him early, he can change the future in his favor. This would force Barry and Clark to work together to stop the Reverse Flash's evil plans.