Supergirl is hurt by a kryptonite-powered villain sent by Cadmus to attack National City. Superman blames Hank since the kryptonite was stolen from the DEO. In the meantime, Kara's first day at her new job doesn't go as planned when she meets her new boss.
Supergirl and the DEO are assigned to protect the President when an attack on her causes alien vs. human rights in National City to heat up. Alex investigates the case with Maggie Sawyer while Kara fears Mon-El may be responsible.
The Guardian arrives to lend a hand when an alien parasite drains Supergirl of her power. Mon-El contemplates his motives when he considers a new career. Alex faces a new reality.
As Eliza comes to National City for Thanksgiving, Kara turns to Lena for help when Cadmus unleashes a virus that instantly kills aliens, then is asked by Barry Allen and Cisco Ramon for help with an alien invasion on their Earth.
Supergirl goes on high alert when a new villain comes to National City. Meanwhile, Winn's new girlfriend Lyra gets him in trouble with the law and the Music Meister attacks.
Supergirl struggles to decide whether or not to obey the President's orders regarding Rhea's latest actions. Meanwhile, Cat Grant returns to National City.