During Krypton's catastrophe, scientist Zor-El David Krumholtz and his wife Alura evacuate with countless others to Argo City. Zor-El activates a force field that severs a chunk containing the city from Krypton, ensuring it survives the planet’s explosive end. Eight years pass, and Alura gives birth to Kara Milly Alcock. When the separated shard is found to harbor a mineral called Kryptonite, radiation slowly poisons the citizens. After Alura succumbs to Kryptonite poisoning, Zor-El decides to send Kara and her dog Krypto to Earth. On arrival, they are greeted by Kara's cousin Kal-El David Corenswet, living a double life as Clark Kent and Superman. Kara begins to adjust to life on Earth, adopting the moniker Supergirl as she learns to navigate her new home.
In the present, Kara travels with Krypto to a string of planets to celebrate her 23rd birthday, and Superman often calls, worried that she stays off-world too much. During one stop, Kara meets Ruthye Marye Knoll, the last survivor of her family, murdered by Krem of the Yellow Hills, leader of a ruthless gang known as the Brigands. Ruthye asks for Kara’s help in seeking vengeance, but Kara declines. Ruthye Eve Ridley becomes a driving presence in the story, even as Kara remains wary.
Krem hijacks Kara’s ship along with several Brigands and shoots Krypto with a poisonous dart, dooming him to a short time left. Learning that Krypto has only three days to live, Kara resolves to pursue Krem to retrieve a crucial antidote that he keeps on him, and she reluctantly takes Ruthye along as a companion. After a brief clash with the Sklarian Raiders, Kara interrogates them and learns that Krem is on the planet Bilquis. There, a local couple, Bomar and Mareck, reveal that the Brigands have been kidnapping young women to force them into marriages. Mareck attempts to drug Kara to trade her and Ruthye for their daughter Sarna, but Kara resists and fights the Brigands, aided by the bounty hunter Lobo, who is targeting the Brigands’ lieutenant Drom Baxton Diarmaid Murtagh. Amid the chaos, Kara stops Ruthye from killing Krem, allowing him to escape after killing Bomar and his family. Guilt-ridden, Kara decides to press forward alone, and she is guided by several local aliens toward the Brigands’ location on the planet Barenton. However, Kara is weakened by Barenton’s green sun, and Ruthye secretly follows and tends to her.
Ruthye is later captured by the Brigands and taken aboard, where Lobo is also imprisoned. Ruthye manages to escape her cell and free Lobo, but is soon stopped by Krem at the topside. Kara, having recovered after Barenton rotates to a yellow sun and donning her Supergirl suit, returns with Lobo’s help to defeat the Brigands and free the captive women. She pleads with Ruthye not to kill Krem, convincing her that vengeance won’t heal her pain. Ruthye walks away, and Supergirl retrieves Ruthye’s sword before delivering a final blow to Krem herself to secure the antidote and get back to Krypto in time. Kara then invites Ruthye to join her for the rest of her birthday week as they begin to heal together.
Some time later, Supergirl reunites with Superman on Earth, expressing a desire to stay for the long term and affirming that the planet is now her home.
