After 12 years of keeping her powers a secret on Earth, Kara Zor-El, Superman's cousin, decides to finally embrace her superhuman abilities and be the hero she was always meant to be.

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.

Kara’s friends must find a way to save her life when a parasitic alien attaches itself to her and traps her in a dream world where her family is alive and her home planet was never destroyed. Also, Alex, Hank and the DEO must fend off a Kryptonian attack while Kara is out of commission.

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).