When a new threat emerges in National City, Kara/Supergirl teams up with her cousin, Clark Kent/Superman, to stop it. Kara is thrilled to have family in town but it leaves Alex feeling a bit left out. Meanwhile, Hank and Supergirl are stunned by the pod that came crashing to Earth.

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.

An attack is made on the President as hot-button, alien vs. human rights issues heat up in National City. Supergirl and the DEO are assigned to protect the President and bring in the responsible party. Alex teams up with Detective Maggie Sawyer to investigate the case while Kara searches for a recently escaped Mon-El, who she fears may be the alien behind the assault.

When Kara and Alex investigate the murder of an unregistered alien, the trail leads to an alien fight club run by Roulette, the ringmaster who commands aliens to fight in mortal combat for the entertainment of rich humans. While trying to stop the fighting, Supergirl and Martian Manhunter find themselves up against a surprising opponent. Meanwhile, Hank is thrilled to have found another Martian and tries to get to know M'Gann better. Supergirl takes Mon-El under her wing and begins to train him.

Supergirl must beat a ruthless new gang who has been armed with dangerous new alien technology. When Cadmus sends a video to the DEO, the team realizes Cadmus is the one staffing the criminals for a secret mission. Meanwhile, Kara gets Mon-El a job as an intern at CatCo, James makes an important decision and Lena invites Kara to attend one her fundraisers.

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. Barry Allen and Cisco Ramon seek Kara’s help with an alien invasion on their Earth. The crossover continues on The Flash S03E08, Arrow S05E08, and DC's Legends of Tomorrow S02E07.

When Kara investigates the story of a missing woman, she and Mon-El end up being thrust through a portal to another planet where the downtrodden are sold as slaves.

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.

Mr. Mxyzptlk, a magical imp, wreaks havoc on National City after being spurned by Kara. Mon-El 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.

As Alex searches for Jeremiah and Kara investigates a series of alien kidnappings, the sisters realize they must break the rules to foil a new Cadmus plot. In an effort to get Snapper Carr to run a story that would help her stop Cadmus, Kara agrees to set up an interview between Snapper and Supergirl.

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.

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.

The DEO investigates a Phorian woman who uses her telekinetic powers to cause rampage. James tracks down her son, Marcus, who refuses to speak with anyone but James, who spends time bonding with him. With Rhea's encouragement, Lena completes the matter transporter, which Rhea activates, causing Marcus to nearly destroy the office with his powers.

The Daxamites launch a full invasion of National City, killing and arresting civilians. They also attack the DEO, but Alex and Winn manage to escape. Mon-El learns that he has to marry Lena in order to unite the people of Earth with Daxam.

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