With Astra in captivity at the DEO, her husband, Non, captures Hank, leading to a tense standoff between the two sides. Also, Kara continues to refute Cat's allegations that she is Supergirl.

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.

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).

When Jeremiah Danvers is rescued from Cadmus, Alex and Kara are thrilled to have their father back. The Danvers arrange a family dinner to celebrate but things go awry when a suspicious Mon-El starts to question Jeremiah about his sudden return.

Supergirl grapples with whether or not to obey the President's orders regarding Rhea's latest actions. Meanwhile, Cat Grant returns to National City.

Eliza throws Alex and Maggie a wedding shower, which causes Maggie to reach out to her estranged father. Supergirl joins J’onn on a personal mission.

Struggling to heal from her injuries inflicted by Reign, Supergirl remains in a dreamlike state, unable to be reached. Mon-El recruits one of the Legion members, Brainiac-5, to try to bring her back. Meanwhile, Reign continues her rampage on the city so the DEO teams up with the Legion of Superheroes to try to stop her.

When Winn’s father dies, his estranged mother, Mary, reappears trying to reconnect and to explain why she abandoned him all those years ago. Winn is too embittered from his rough childhood to forgive her but when a copycat Toyman attacks, the two must work together to stop him. Mon-El tells Kara something important about the Worldkillers, and Alex becomes suspicious of Myr'nn’s recent behavior.

Supergirl is stunned to discover that a part of Krypton survived. Meanwhile, Alex is attacked while out with Ruby, and Lena considers how far she will go to keep Reign contained.

Ben Lockwood didn't always hate aliens. Through a series of incidents, and input from his anti-alien father, Ben slowly transforms from a mild-mannered professor into the villainous Agent Liberty of today.

Secretly furloughed from prison due to failing health, Lex Luthor visits his sister, Lena, to seek her help finding a cure. Savvy as ever, Lena is suspicious of Lex's motives but when she's faced with a life and death situation, she must decide how she truly feels about her brother. Meanwhile, Supergirl and J'onn face off against Manchester Black. James' sister Kelly comes to town.

Kara is surprised to find that CatCo has a new owner who has brought in a star reporter. New couples emerge and explore their budding relationships while J’onn J’onzz receives an unexpected visitor.

As the stakes with Lex are raised higher than ever before, Lena must decide how far she is willing to go to stop her brother. Meanwhile, Supergirl and the team are faced with a challenge unlike anything they've ever dealt with before and it brings Alex to her breaking point.

Lena is uncertain about using her magical abilities to help Supergirl retrieve the second totem from Nyxly. William struggles to write a story on the Super Friends that makes both the heroes and Andrea happy. Meanwhile, Kelly is thrilled Esme has found a new home, but things go awry and the little girl's future is put in danger.