When a new threat emerges in National City, Kara/Supergirl teams up with her cousin, Clark Kent/Superman, to stop it. Kara is thrilled to have family in town but it leaves Alex feeling a bit left out. Meanwhile, Hank and Supergirl are stunned by the pod that came crashing to Earth.
CADMUS attacks National City with a Kryptonite-powered villain who ends up seriously hurting Supergirl. Superman blames Hank because the Kryptonite was stolen from the DEO. Meanwhile, Kara’s first day at her new job doesn’t go as planned after she meets her new boss, Snapper Carr.
An attack is made on the President as hot-button, alien vs. human rights issues heat up in National City. Supergirl and the DEO are assigned to protect the President and bring in the responsible party. Alex teams up with Detective Maggie Sawyer to investigate the case while Kara searches for a recently escaped Mon-El, who she fears may be the alien behind the assault.
When Kara and Alex investigate the murder of an unregistered alien, the trail leads to an alien fight club run by Roulette, the ringmaster who commands aliens to fight in mortal combat for the entertainment of rich humans. While trying to stop the fighting, Supergirl and Martian Manhunter find themselves up against a surprising opponent. Meanwhile, Hank is thrilled to have found another Martian and tries to get to know M'Gann better. Supergirl takes Mon-El under her wing and begins to train him.
Supergirl must beat a ruthless new gang who has been armed with dangerous new alien technology. When Cadmus sends a video to the DEO, the team realizes Cadmus is the one staffing the criminals for a secret mission. Meanwhile, Kara gets Mon-El a job as an intern at CatCo, James makes an important decision and Lena invites Kara to attend one her fundraisers.
The Guardian debuts to lend a hand after a parasite alien drains Supergirl of her power. Mon-El considers a less than desirable new career which then leads him to contemplate his motives. Alex struggles with a new reality.
While Guardian tries to clear his name after being accused of a murder committed by another vigilante, Supergirl heads out on a solo mission to rescue Mon-El who has been captured by CADMUS. While fighting to free Mon-El, Supergirl comes face to face with Cyborg Superman.
Eliza comes to town to celebrate Thanksgiving with her daughters. Alex decides it’s time to come out to her mother; Kara is shocked when Eliza suggests Mon-El has feelings for her, and Winn and James consider telling Kara the truth about the Guardian. Meanwhile, CADMUS unleashes a virus that instantly kills any alien in the vicinity so Kara enlists an unexpected ally – Lena Luthor. The epic superhero crossover kicks off tonight when Barry Allen and Cisco Ramon seek Kara’s help with an alien