Cuando una nueva amenaza emerge en National City, Kara / Supergirl forma equipo con su primo, Clark Kent / Superman, para detenerla. Kara se siente emocionada de tener familia en la ciudad pero eso deja a Alex sintiéndose un poco desplazada. Mientras tanto, Hank y Supergirl están sorprendidos por la nave que llegó a la Tierra.

Cadmus ataca National City con un villano cuyos poderes vienen de la kryptonita y que termina hiriendo seriamente a Supergirl. Superman culpa a Hank porque la kriptonita fue robada del DEO. Mientras tanto, el primer día de Kara en su nuevo trabajo no sale como estaba planeado después de conocer a su nuevo jefe, Snapper Carr.

Un ataque contra la Presidenta hace de botón rojo y los problemas de extraterrestres contra derechos humanos se calientan en National City. Supergirl y el DEO son asignados para proteger a la Presidenta y encontrar a los responsables. Alex forma equipo con la Detective Maggie Sawyer para investigar el caso mientras Kara busca al recientemente escapado Mon-El, el cual ella teme que sea el extraterrestre que hay detrás del ataque.

Cuando Kara y Alex investigan el asesinato de un extraterrestre no registrado, la pista las lleva a un club de la lucha extraterrestre regentado por Roulette, la maestra de pista que obliga a extraterrestres a pelear en combates a muerte para entretener a humanos ricos. Mientras intentan detener las peleas, Supergirl y Martian Manhunter se encuentran a sí mismos contra un sorprendente oponente. Mientras tanto, Hank está emocionado por haber encontrado a otro marciano e intenta conocer mejor a M’Gann. Supergirl coge a Mon-El bajo su protección y empieza a entrenarlo.

Supergirl debe vender a una despiadada nueva banda que ha sido armada con peligrosa tecnología alienígena. Cuando Cadmus le envía un vídeo al DEO, el equipo se da cuenta de que es Cadmus quien está armando a los criminales para una misión secreta. Mientras tanto, Kara consigue un trabajo para Mon-El como interno en CatCo, James toma una decisión importante y Lena invita a Kara a asistir a una de sus recaudaciones de fondos.

The Guardian debuts to lend a hand after a parasite alien drains Supergirl of her power. Mon-El considers a less than desirable new career which then leads him to contemplate his motives. Alex struggles with a new reality.

While Guardian tries to clear his name after being accused of a murder committed by another vigilante, Supergirl heads out on a solo mission to rescue Mon-El who has been captured by Cadmus. While fighting to free Mon-El, Supergirl comes face to face with Cyborg Superman.

Eliza comes to town to celebrate Thanksgiving with her daughters. Alex decides it’s time to come out to her mother; Kara is shocked when Eliza suggests Mon-El has feelings for her, and Winn and James consider telling Kara the truth about the Guardian. Meanwhile, Cadmus unleashes a virus that instantly kills any alien in the vicinity so Kara enlists an unexpected ally – Lena Luthor. The epic superhero crossover kicks off tonight when Barry Allen and Cisco Ramon seek Kara's help with an alien invasion on their Earth.

The crossover continues on The Flash S03E08 Invasion! (II), Arrow S05E08 Invasion! (III) and DC's Legends of Tomorrow S02E07 Invasion! (IV).

Kara is moved by the story of a missing woman named Izzy and decides to investigate despite Snapper Carr's order to leave it alone. Kara takes Mon-El with her to the last place Izzy was seen and the duo find themselves thrust through a portal to another planet, Slaver's Moon, where the downtrodden are sold as slaves. The leader of the trafficking ring is none other than Roulette. To make matters worse, Slaver's Moon has a red sun, which means Kara and Mon-El are stripped of their powers and stuck on the planet with no way home. Meanwhile, back on Earth, Alex blames herself for Kara's disappearance, fearing she's become too focused on her new relationship with Maggie and too complacent in watching out for her sister.

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.

Armek, a White Martian, descends on National City intent on taking M’gann back to Mars to face her punishment as a traitor. Hank and Supergirl determine the best way to keep M’gann safe is to bring her to the DEO. However, when it is revealed that Armek shape-shifted into M’gann and is now loose in the building, the team realize he could be disguised as any one of them.

After Metallo breaks out of prison and frees Lillian Luthor, the police blame Lena for his escape and arrest her. Despite overwhelming evidence, Kara refuses to believe her friend is guilty and fights to clear Lena’s name. Flashbacks reveal how Lena came to be a Luthor.

When Mr. Mxyzptlk, a magical imp, shows up on Earth and declares his love for Kara, she tries to let him down easy, thinking him harmless. However, he decides it’s a challenge and starts to wreak havoc on National City. Mon-El has seen beings like Mr. Mxyzptlk on Daxam and knows how dangerous they can be. He and Kara argue over how to get rid of Mr. Mxyzptlk, further straining their relationship. Meanwhile, Alex and Maggie celebrate their first Valentine’s Day together.

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.

A new villain comes to National City, putting Supergirl on high alert. Meanwhile, Winn’s girlfriend, Lyra, gets Winn in trouble with the law. Maggie attempts to help Winn but old loyalties get in the way. The Music Meister attacks Supergirl.

The crossover continues on The Flash S03E17 Duet (II).

A large bounty is put out on Supergirl and aliens from far and near attack National City intent on taking out the woman of steel. Alex and Maggie run into Maggie’s ex-girlfriend, Emily, who is in town for a week. Hank gets an interesting order from President Marsdin.

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.

Alex is kidnapped and the kidnapper threatens to kill her unless Supergirl releases a notorious criminal from prison. Supergirl and Maggie have always had different approaches to apprehending criminals but this time they must work together to save Alex. Meanwhile, Rhea has an interesting proposal for Lena.

When an alien attacks National City, Supergirl and the DEO learn the alien is a Phorian, an otherwise peaceful race with telekinetic powers. Guardian gets a lead on the Phorian's address but instead of finding the culprit, he finds a very scared boy named Marcus. Marcus will only trust James so it is up to Guardian to stop the attacks on the city. Rhea's plan escalates.

Supergirl grapples with whether or not to obey the President's orders regarding Rhea's latest actions. Meanwhile, Cat Grant returns to National City.

Supergirl challenges Rhea to battle to save National City. Meanwhile, Superman returns and Cat Grant offers Supergirl some sage advice.