Born on the planet Krypton, Kara Zor-El escaped amid its destruction years ago. Since arriving on Earth, she's been hiding the powers she shares with her famous cousin. But now at age 24, she decides to embrace her superhuman abilities and become the hero she was destined to be, Supergirl.
After a seemingly Kryptonian pod crashes in National City, Superman comes to visit his cousin. While the two of them try to determine if Lena Luthor--Lex's sister--is up to no good, Kara wrestles with her personal life.
Supergirl and the DEO are called on to protect the President when she comes to National City to sign her Alien Amnesty Act. However, a hostile alien threatens to kill the President and anyone who gets in its way. Meanwhile, Alex meets Maggie Sawyer, a detective with the NCPD's science division, and Snapper challenges James' authority.
While Hank tries to bond with Megan, Supergirl and Alex discover that a woman named Roulette is running an underground fight club using aliens as gladiators. Meanwhile, Mon-El convinces Winn to take him out for a night on the town.
Cadmus provides a gang of crooks with alien weaponry in an attempt to spread fear and panic among the populace. Meanwhile, Kara tries to mentor Mon-El with minimal success, and James decides that he wants to be a superhero.
Supergirl battles a scientist who has been possessed by an alien parasite, giving the ability to drain the lifeforce from anyone he touches. Meanwhile, Alex comes out to Kara, and the Guardian makes his first public appearance.
When the Danvers celebrate Thanksgiving, Alex tries to find the right time to tell her mother Eliza that she's gay. Meanwhile, Lena is forced to choose when Supergirl tells her that Lillian plans to unleash a virus that will wipe out every alien in the city.
Crossover among four CW shows: Supergirl "Medusa"; The Flash "Invasion!"; Arrow ‘Invasion!"; DC's Legends of Tomorrow "Invasion!"
When a girl disappears, Kara discovers a pattern of missing people and goes looking with Mon-El... and they both end up on an alien planet under a red sun which renders them powerless. Meanwhile, Winn has a brush with death, and Alex and Maggie have their first disagreement.
Livewire escapes prison, but the DEO soon realizes that she wasn't a willing escapee. Meanwhile, Megan collapses and Hank refuses to mind-meld with her to find out what is wrong with her, and James considers telling Kara that he's Guardian.
M'gann's White Martian mate Armek comes to Earth to bring her back to face justice for her "treachery' When she takes refuge in the DEO, Armek infiltrates the building and uses his shapeshifting powers to spread confusion.
It's Valentine's Day, and Kara finds herself dealing with the amorous advances of Mxyztplk, a fifth-dimensional being with unlimited magical powers. Meanwhile, Alex discovers that Maggie hates Valentine's Day, while an alien woman hits on Winn.
The DEO manages to rescue Jeremiah from Cadmus, but Mon-El's suspicions soon drive a wedge between him and the Danvers sisters. Meanwhile, Cadmus continues with its master plan to cleanse the planet of alien influence.
Alex refuses to obey Hank's orders to stand down and sets out to find Cadmus and protect Jeremiah. Meanwhile, Kara takes drastic steps when Snapper refuses to publish her story intended to protect the remaining aliens on Earth from Cadmus.
Mon-El's parents arrive to bring home and help restore Daxam to its former glory... and Supergirl realizes that Mon-El has been lying to her. Meanwhile, Winn discovers that Lyra has set him up when he's the prime suspect in a museum robbery. The Music Meister puts Supergirl into a coma and the story line concludes in The Flash: "Duet", Season 3, Episode 17.
Someone hires bounty hunters to kill Supergirl, and Mon-El believes that his parents are responsible. Meanwhile, Maggie and Alex run into Maggie's old girlfriend, and President Marsdin gives express orders to Hank not to attack the Daxamites.
Lena's ex Jack Spheer arrives in National City to roll out a new nanite medical procedure. However, Kara ;soon realizes that something more is going on when one of the human test subjects die under mysterious circumstances. Meanwhile, Lyra comes between Winn and James in their crimefighting efforts.
Alien refugees, the Phorians, trigger telekinetic quakes every time that Lena and Rhea activate the portal. While James tries to get through to one alien boy who knows where the others are, the DEO tries to find the portal before it's too late for National City.
Alex takes over as Acting Director of the DEO as the Daxamites take over National City, open fire on Air Force One, and recruit a familiar face to their side. Meanwhile, Cat Grant returns to National City to inspire Supergirl and the populace.