Supergirl is an action-adventure drama based on the DC Comics character Kara Zor-El, Superman's (Kal-El) cousin who, after 12 years of keeping her powers a secret on Earth, decides to finally embrace her superhuman abilities and be the hero she was always meant to be.
After losing Mon-El, Kara decides to give up her human life and dedicate herself full-time to being Supergirl. Meanwhile, a new menace threatens National City, and real estate mogul Morgan Edge makes a bid to buy up CatCo. Also, Alex confesses a secret to Maggie, a citizen of National City has a mysterious connection to Kara, and Lena makes a bold move.
Kara takes Alex home to Midvale after Alex and Maggie break up. While Alex deals with the end of her relationship, she and Kara remember the first time that they bonded as sisters while solving the murder of a fellow high school student.
The DEO rescues Mon-El from a spaceship buried in 12,000 years of rock, but Mon-El remains strangely silent about how he got there. Meanwhile, Hank takes M'yrnn to the park, and Sam goes to her mother Patricia for answers about her birth.
Rather than wallow in self-pity, Kara and Alex go to Barry Allen and Iris West's wedding... only to find the ceremony interrupted by Nazi soldiers and villains from Earth-X including a mysteriously strong superpowered female warrior.
Supergirl learns that a mysterious Kryptonian symbol suddenly appearing around the city heralds the appearance of the World Killer, Reign. She's a Kryptonian whose powers exceed Supergirl's... and who is determined to bring judgment to a sinful world. The tension between Lena and Morgan Edge continues to build.
Supergirl and Saturn Girl are forced to recruit two female metas to find a prisoner on Fort Rozz, which is orbiting a sun that emits radiation fatal to males. Meanwhile, Alex babysits Ruby while Sam goes on a work trip.
Morgan believes that a recent attempt on his life was made by Lena. When Lena is poisoned, Kara steps in to find out who is responsible for the escalation in hosility. Meanwhile, Sam turns to Alex for help determining the cause of her blackouts.