When Winn and the team discover an alien ship has crash landed deep underwater beneath National City, Kara/Supergirl is called in to investigate. Meanwhile, Hank attempts to bond with his father, Myr'nn. Samantha, eager for some understanding of the changes she has been experiencing, looks to her estranged mother, Patricia Arias, for answers.

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.

Struggling to heal from her injuries inflicted by Reign, Supergirl remains in a dreamlike state, unable to be reached. Mon-El recruits one of the Legion members, Brainiac-5, to try to bring her back. Meanwhile, Reign continues her rampage on the city so the DEO teams up with the Legion of Superheroes to try to stop her.

As Reign continues to terrorize the city, Supergirl teams up with Saturn Girl, and the two recruit Supergirl’s former enemies, Livewire and Psi, to form a team for a mission to Fort Rozz to recover a prisoner who has information on how to defeat Reign once and for all. Meanwhile, Alex babysits Ruby.

The DEO captures a second Worldkiller, Purity. Supergirl and Alex use very different methods of interrogation with Purity in the hopes of finding out how to defeat Reign. However, Purity escapes and attacks the city’s subway tunnels. Meanwhile, J’onn, Winn and Mon-El band together to fix the Legion ship.

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.

When Reign starts hunting Ruby, Supergirl and Alex work together to keep her safe. Supergirl and J'onn look to Sam’s mother for advice on how to stop Reign and come away with some shocking news.

Supergirl and team take on Selena in an epic battle for Earth.