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.
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.
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.
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.
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.
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.
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.
I think Supergirl and Black Widow would be an interesting pairing. Black Widow is a skilled spy and fighter, while Supergirl has superpowers. They could learn from each other. Black Widow could teach Supergirl some stealth techniques, and Supergirl could protect Black Widow during battles with her super strength and speed.
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.
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.