Kara's Thanksgiving may be ruined when she suspects her foster mother, Dr. Danvers, who is coming to town, disapproves of her new role as a superhero. Also, when an accident transforms a volatile CatCo employee into the villainous Livewire, she targets Cat and Supergirl.

Kara goes toe-to-toe with Astra when her aunt challenges Kara’s beliefs about her mother. Also, Cat is threatened with being removed as the CEO of CatCo after a hacker exposes her private and damaging emails.

Kara must help Hank face his painful past when a White Martian, a member of the alien race that wiped out his people, kidnaps Senator Miranda Crane, an anti-alien politician. Also, Cat's estranged son, Adam, arrives in National City.

Kara must find a way to free her friends when Non and Indigo use mind control to turn National City’s citizens into their own army.

CADMUS attacks National City with a Kryptonite-powered villain who ends up seriously hurting Supergirl. Superman blames Hank because the Kryptonite was stolen from the DEO. Meanwhile, Kara’s first day at her new job doesn’t go as planned after she meets her new boss, Snapper Carr.

After Livewire seemingly breaks out of prison, Supergirl is intent on recapturing her. After training Mon-El, Supergirl takes him with her when she sees Livewire attack the NCPD but things go awry when Mon-El puts Supergirl before the citizens of National City. Meanwhile, James decides to come clean with Kara and M’Gann, has a psychic attack and collapses into a coma.

When Jeremiah Danvers is rescued from Cadmus, Alex and Kara are thrilled to have their father back. The Danvers arrange a family dinner to celebrate but things go awry when a suspicious Mon-El starts to question Jeremiah about his sudden return.

Lena’s ex-boyfriend, Jack Spheer, comes to National City to unveil his big breakthrough in nano-technology, which has the potential to eradicate all diseases. Lena asks Kara to attend Jack’s conference with her for support. When Kara sees Snapper in attendance she’s inspired to tap back into her reporter skills and questions Jack on his discovery, which ultimately leads to a bigger investigation that puts everyone in danger.

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 Danver sisters closer together.

Supergirl investigates a mysterious symbol popping up all over National City, tracing its origins back to an ancient prophecy and the mark of the World Killer, Reign. Meanwhile, the tension between Lena and Morgan Edge continues to build, causing James to step in and offer up some protection, and possibly igniting a spark in the process.

When Winn’s father dies, his estranged mother, Mary, reappears trying to reconnect and to explain why she abandoned him all those years ago. Winn is too embittered from his rough childhood to forgive her but when a copycat Toyman attacks, the two must work together to stop him. Mon-El tells Kara something important about the Worldkillers, and Alex becomes suspicious of Myr'nn’s recent behavior.