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.
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.