I tredje sæsons premiereafsnit håndterer Kara tabet af Mon-El ved at fokusere al sin energi på at være Supergirl og på den gådefulde, nye trussel mod National City. Alex bekender en hemmelighed for Maggie om deres forestående bryllup.

National City angribes af Psi, der er en tyv, hvis psykiske kræfter kan lamme folk gennem deres frygt, og som viser sig at være en formidabel modstander for Supergirl. Imens har James og Lena nået et dødvande, og Samantha begynder sit nye job ved L-Corp.

Eliza throws Alex and Maggie a wedding shower, which causes Maggie to reach out to her estranged father. Supergirl joins J’onn on a personal mission.

Kara investigates a secretive new group whose leader, Thomas Coville, has a mysterious connection to Supergirl. Meanwhile, Samantha feels like she's letting Ruby down, and J'onn confesses an old secret.

When multiple children get sick from lead poisoning, Morgan Edge points the finger at Lena and blames her creation of the lead bomb she made to save National City from the Daxamites. While Lena knows she never intended any harm, she fears there may have been a flaw in her design, leaving her responsible. Kara teams up with Samantha to clear Lena’s name, but it turns out to be harder than they thought. Meanwhile, Alex and Maggie make a crucial decision about the future of their relationship.

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.

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.

Barry and Iris’s wedding brings the gang together, but things go awry when villains from Earth-X attack the ceremony. All of the superheroes band together with help from their super friends like Citizen Cold, The Ray, Felicity Smoak, Iris West and Alex Danvers to take on their most formidable villains yet. Earth’s mightiest heroes – Green Arrow, Supergirl, The Flash and White Canary – lead their teams into battle to save the world.

The crossover continues on Arrow S06E08 Crisis on Earth-X (II), The Flash S04E08 Crisis on Earth-X (III) and DC's Legends of Tomorrow S03E08 Crisis on Earth-X (IV).

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.

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.

Someone tries to kill Morgan Edge and he barely survives. He accuses Lena of being behind the attempt and vows to destroy her. When Lena fears her hatred for Morgan will take her to the Luthor dark side, Kara steps in to help her friend. Meanwhile, after Sam realizes she’s losing time, she confides in Alex who decides to run some medical tests to see if she can find out what’s going on with her new friend.

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.

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.

Myr'nn inadvertently causes psychic disturbances at the DEO; Supergirl must work with J'onn to contain the chaos; Mon-El begins training Kara in fighting techniques he's learned in the future.

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.

When Tanya, a disciple of Coville's, escapes from what's left of his cult, she gives Kara and James a journal that could hold the key to saving Sam. Someone learns Guardian's identity and threatens to expose James if he doesn't do what they ask. James contemplates what it means to be a black vigilante without a mask in America.

Supergirl is stunned to discover that a part of Krypton survived. Meanwhile, Alex is attacked while out with Ruby, and Lena considers how far she will go to keep Reign contained.

Kara makes a major life decision. Meanwhile, J'onn finds out that special DEO-caliber guns have hit the streets of National City.

Supergirl learns the true depth of Serena's nefarious plans for Earth. Supergirl, Mon-El and Alura must devise a plan to stop her before Serena gets to Earth. J'onn prepares to say goodbye to his father.

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