In season four, Supergirl is facing a bigger threat than she’s ever faced before – a new wave of anti-alien sentiment, spreading across National City that’s fomented by Agent Liberty. As Kara mentors a new reporter at CatCo, Nia Nal, and tries to use the power of the press to shine a light on the issues threatening to tear the city apart, Supergirl takes to the skies to battle the many villains who rise up in this era of divisiveness.
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 may be more sinister than she expected.
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.
Colonel Haley makes a surprising decision regarding Supergirl. Kara writes a series of articles highlighting aliens in National City in the hopes that humans will stop being so fearful of them. Unfortunately, the article puts some of the aliens in harm’s way.
Everyone gathers for Thanksgiving but Kara is feeling down after her televised debate with Ben Lockwood about the anti-alien sentiment coursing through National City. Meanwhile, James and Lena argue about the best way to handle the Children of Liberty.
James falls in deeper with the Children of Liberty in his efforts to meet Agent Liberty. Meanwhile, Supergirl and Manchester Black follow a lead on Agent Liberty’s location, but things take a dark turn. Lena kicks off her first set of trials.
Nia has a powerful dream about Agent Liberty but refuses to look at it as a prophetic dream, Kara and Brainy try to persuade Nia to embrace her destiny, and Manchester Black pays Ben Lockwood a menacing visit.
Third and last part of the crossover event with The Flash and Arrow.
Colonel Haley is upset after Supergirl responds to a distress call from a Navy ship that turned out to be a deadly alien attack. Colonel Haley reclaims the site as DEO territory and demands that Supergirl step aside. After Supergirl refuses to be told what to do, Haley refocuses her energy on finding out Supergirl’s true identity and begins to interrogate all DEO agents, including Alex.
Kara joins Nia on a trip to Nia’s hometown to visit her family during the town’s annual Harvest Festival. While home, Nia’s mother encourages her daughter to embrace her destiny. Meanwhile, Alex deals with a street drug that is turning people violent and giving them temporary superpowers.
With his P.I. shingle newly hung outside his office, J'onn welcomes new clients. Trying to take her mind off what happened at the DEO, Kara decides to team up with J'onn on his latest assignment, which unfortunately ends up tying directly into Alex's current investigation that involves the villain Menagerie. Meanwhile, Lena shares some news with James, but his reaction isn't what she expected. Nia invites Brainy to her Valentine's Day party.
Manchester Black breaks out of prison with the help of his new team, The Elite, who are set on punishing the anti-alien forces. Supergirl pulls double duty as she tries to apprehend Manchester Black and his team as well as deal with a shocking new development with Ben Lockwood.
Between Ben Lockwood’s new push to stir up the anti-alien movement and the Elite’s desire to target Lockwood and his minions, Supergirl is concerned about the safety of the American people – both human and alien. When Lockwood organizes a rally, the aliens decide to peacefully protest. Brainiac and J'onn join the alien march while Supergirl and Dreamer patrol to keep everyone safe. Meanwhile, James picks up his camera again to cover the march for CatCo, and Hayley assigns Alex a job that clashes with her beliefs. When the Elite and Ben Lockwood stir up trouble at the rally, Supergirl is forced to take a stand.
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.
Supergirl must deal with the destructive aftermath of Lex's nefarious plans. Shocked at what Lex has created, Supergirl faces her biggest challenge yet.
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.