The Dominators could be a good choice too. They are a powerful alien race. They might see both Flash and Supergirl as threats to their plans of conquest. They could use their advanced technology to neutralize Supergirl's powers and try to trap Flash in a time - loop or something similar.
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.
Reverse - Flash would also be a likely candidate. He could team up with one of Supergirl's foes, like Reactron. Together, they could cause chaos. Reverse - Flash could mess with the timeline to make things difficult for Flash and Supergirl, while Reactron attacks Supergirl directly.
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.
Kabuto could be a likely villain. He's very intelligent and has a thirst for power. He could use his knowledge of jutsu and his ability to manipulate others to try and steal The Flash's speed force. He might think that by combining it with his own powers and ninja techniques, he could become invincible.
The Reverse Flash could be an exciting villain in a Supergirl Arrow crossover. His ability to move at super - speeds would make him a formidable opponent for Supergirl. He could also mess with Arrow's timeline, creating chaos in both their worlds. Imagine him going back in time to prevent Supergirl from arriving on Earth or changing events that led to Arrow becoming a vigilante. His manipulative nature and his connection to the Speed Force would bring a whole new level of complexity to the crossover story.
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.
The Reverse - Flash would be really interesting. He could target both Batman and the Flash. For the Flash, he's a long - time nemesis, but for Batman, he'd be a new and extremely dangerous threat. His ability to manipulate the speed force and time could put Gotham in chaos in ways Batman has never seen before. And he could use his knowledge of the Flash to try and set traps for both heroes.
The Joker could be a really interesting villain in this fan fiction. He could somehow find his way to Metropolis and start causing chaos. His insanity and unpredictability would be a challenge for both Red Hood, who has a history with him, and Supergirl, who has never faced such a deranged foe. The Joker could also try to drive a wedge between them to make the situation more difficult.
I think Eobard Thawne, the Reverse - Flash, could be really interesting. He could use his speed to try and steal Danny's ghost powers. His devious nature and time - traveling abilities would make him a formidable foe. He might see Danny's powers as a way to enhance his own and become even more powerful. And Danny would have to use his unique ghostly skills, like his ability to phase through objects and fly, to outwit the Reverse - Flash.
Darkseid is another option. His power and his desire to conquer Earth could bring Batman and Superman together. He could target both Metropolis and Gotham, and his presence would require the two heroes to combine their skills. Batman's strategic mind and Superman's brute strength would be needed to face this powerful foe.
Reverse - Flash could be a great antagonist. He could team up with one of Supergirl's foes like Reactron. Reverse - Flash's speed and devious nature combined with Reactron's ability to emit radiation could pose a serious threat to Supergirl and Flash. They would have to figure out how to stop these two villains from causing chaos.
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.