Twenty-four-year-old Kara Zor-El, cousin of Superman, who was taken in by the Danvers family when she was 12 after being sent away from Krypton, must learn to embrace her powers after previously hiding them.
Supergirl's powers are put to the test when one of Superman's most formidable enemies, Reactron, shows up in National City to take her down. In the meantime, Cat makes plans to run an expose on Supergirl.
Stress makes Kara go too far during a training exercise against a military cyborg commissioned by General Sam Lane, while Cat's mother comes to visit and Winn helps Alex investigate her father's death.
Kara does her best to support Winn when he hears that his father Winslow Schott Sr. breaks out of prison. His father looks for Winn for a reason to become like him. Cat offers Lucy a job working at CatCo and Alex asks Hank to use his powers to find out and uncover Maxwell Lord's plans.
Kara helps Hank face his painful past when a White Martian, who wiped out all of the Green Martians from Mars, kidnaps Senator Miranda Crane who is an anti-alien politician. Adam Foster who is Cat's estranged son arrives in National City.
Kara travels to the Fortress of Solitude hoping to find information on how to defeat Indigo, a being from her past who can travel through the Internet. In the meantime, James and Lucy reach a crossroads in their relationship.
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.
Kara deals with the loss of Mon-El by focusing her energy on being Supergirl and concentrating on a mysterious new threat. Alex confesses a secret to Maggie. A citizen of National City has a mysterious connection to Kara. Lena makes a bold move.
Kara and Alex head home to Midvale for a little R&R. While there, Kara recalls a painful memory of a childhood friend's death and how that traumatic experience brought the Danvers sisters closer together.
Supergirl and Imra have different ideas on how to stop the third Worldkiller, Pestilence. However, when both Alex and Winn are seriously injured by Pestilence, Supergirl and Imra team up to stop the destruction.
Still reeling after learning about Lena's secret, Supergirl asks Guardian for a favor that could alter his relationship with Lena forever. Meanwhile, with all three Worldkillers united, Supergirl and the team brace for an epic battle.