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.

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 invasion on their Earth.

The crossover continues on The Flash S03E08 Invasion! (II), Arrow S05E08 Invasion! (III) and DC's Legends of Tomorrow S02E07 Invasion! (IV).

As Alex searches for Jeremiah and Kara investigates a series of alien kidnappings, the sisters realize they must break the rules to foil a new Cadmus plot. In an effort to get Snapper Carr to run a story that would help her stop Cadmus, Kara agrees to set up an interview between Snapper and Supergirl.

Lena’s ex-boyfriend, Jack Spheer, comes to National City to unveil his big breakthrough in nano-technology, which has the potential to eradicate all diseases. Lena asks Kara to attend Jack’s conference with her for support. When Kara sees Snapper in attendance she’s inspired to tap back into her reporter skills and questions Jack on his discovery, which ultimately leads to a bigger investigation that puts everyone in danger.

When an alien attacks National City, Supergirl and the DEO learn the alien is a Phorian, an otherwise peaceful race with telekinetic powers. Guardian gets a lead on the Phorian's address but instead of finding the culprit, he finds a very scared boy named Marcus. Marcus will only trust James so it is up to Guardian to stop the attacks on the city. Rhea's plan escalates.

Kara deals with the loss of Mon-El by focusing all her energy on being Supergirl and the mysterious new threat against National City. Alex confesses a secret to Maggie about their impending nuptials. A citizen of National City has a mysterious connection to Kara, and Lena makes a bold move.