After 12 years of keeping her powers a secret on Earth, Kara Zor-El, Superman's cousin, decides to finally embrace her superhuman abilities and be the hero she was always meant to be.

When Kara’s attempts to help National City don't go according to plan, she must put aside the doubts that she -- and the city's media -- has about her abilities in order to capture an escapee from the Kryptonian prison, Fort Rozz. Also, Cat pressures James to use his connection to Superman to get her an interview with Supergirl.

Kara’s friends must find a way to save her life when a parasitic alien attaches itself to her and traps her in a dream world where her family is alive and her home planet was never destroyed. Also, Alex, Hank and the DEO must fend off a Kryptonian attack while Kara is out of commission.

Supergirl is forced to do battle with an unexpected foe and must risk everything – including her life – to prevent Non and Indigo from destroying every person on the planet.

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.

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.

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

Kara deals with the loss of Mon-El by focusing all her energy on being Supergirl and the mysterious new threat against National City. Alex confesses a secret to Maggie about their impending nuptials. A citizen of National City has a mysterious connection to Kara, and Lena makes a bold move.

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).