Diving back into reporting, Kara welcomes a new cub reporter to CatCo. Meanwhile, James and Lena argue about James’ impending indictment for acting as the vigilante Guardian, while Alex and Brainy struggle to get in sync at the DEO. Supergirl is called into action when remnants of the anti-alien terrorist organization Cadmus try to assassinate pro-alien leaders, but their endgame turns out to be much more sinister than she expected. J’onn relishes his peaceful new life, but an outing with an old friend causes him concern.

A shocking revelation causes chaos in National City. Supergirl sets out to capture Mercy Graves, while Alex takes control at the DEO. Back at CatCo, Kara decides to write an investigative story on Mercy and asks Lena if she can interview her as Mercy has ties to the Luthors. Meanwhile, Brainy meets Nia and the two end up in a precarious situation.

Ben Lockwood didn't always hate aliens. Through a series of incidents, and input from his anti-alien father, Ben slowly transforms from a mild-mannered professor into the villainous Agent Liberty of today.

When Supergirl needs help, Alex asks Lena and Brainiac to team up. Meanwhile, J’onn questions his decision to quit the DEO. However, after running into Manchester Black, he realizes there are a lot of ways to help his fellow aliens during this tumultuous time.

Secretly furloughed from prison due to failing health, Lex Luthor visits his sister, Lena, to seek her help finding a cure. Savvy as ever, Lena is suspicious of Lex's motives but when she's faced with a life and death situation, she must decide how she truly feels about her brother. Meanwhile, Supergirl and J'onn face off against Manchester Black. James' sister Kelly comes to town.

In the wake of Lex Luthor's return, the show flashes back to what he's been doing for the last two years and how his secret machinations and plans have affected Supergirl and Lena.

Kara and Lena head to Stryker's Island to search for clues on how to defeat Lex. At the prison, Kara tries to befriend a nosy prisoner, Steve, who may have insight into what Lex was doing, while Lena studies an array of puzzles Lex left behind in the hopes of discovering his whereabouts. While there, a prison riot breaks out and Kara must find a way to stop the prisoners without revealing her secret identity as Supergirl. Meanwhile, Kelly encourages James to talk to someone for his PTSD, and Alex faces off against Ben Lockwood after he storms the DEO and acquires some powerful weapons to hunt Supergirl.

Kara comes face to face with Red Daughter and the two engage in an epic battle. Determined to find a way to extract the Harun-El, Lena turns to an unlikely source for help - Lillian Luthor. Meanwhile, Alex realizes she's missing parts of her memory, and Brainy, Nia and J'onn set out to track down aliens who have been abducted by Lex.

Mxyzptlk returns with a proposition for Kara – what if she could go back in time and tell Lena her secret before Lex did, would things turn out different? Looking back over key moments throughout the series, Kara must decide if she wants to change history to become friends with Lena again.

As Brainiac lays close to death after trying to stop Lex, Supergirl and team soar in to save him, engaging in an epic battle with Gamemnae. After beating Leviathan, Supergirl turns her attention to Lex who has used the Obsidian platform to brainwash half the world to love him and follow him at all costs, no matter what horrible things he does. Knowing how dangerous this makes her brother, Lena enlists the entire team – Alex, J’onn , Dreamer, Kelly and Brainiac – to help, but Supergirl realizes that the only way to truly stop Lex is to sacrifice herself.

As the stakes with Lex are raised higher than ever before, Lena must decide how far she is willing to go to stop her brother. Meanwhile, Supergirl and the team are faced with a challenge unlike anything they've ever dealt with before and it brings Alex to her breaking point.

When Lex Luthor appears by Nyxly's side, Supergirl and team must deal with the emotional fallout of facing their two biggest foes at the same time. Alex makes plans for the perfect proposal to Kelly, but work keeps getting in the way.