Cast and characters
Melissa Benoist as Kara Zor-El / Kara Danvers / Supergirl: A Kryptonian living in National City, who must embrace her powers after previously hiding them. She assists her adoptive sister Alex as part of the Department of Extra-Normal Operations (DEO) as she discovered the truth that her adoptive father also worked for the DEO so they would not take her, while Alex's co-workers at the DEO help her perfect her powers. Kara worked as Cat Grant's assistant at CatCo. Benoist expressed her excitement over portraying the character, and being able to "[tell] a story about a human being really realizing their potential and their strength". Malina Weissman (seasons 1-2) and Izabela Vidovic (seasons 3-4 & 6) portray a young Kara.
Mehcad Brooks as James "Jimmy" Olsen / Guardian (seasons 1–5; guest: season 6): A former Daily Planet photographer, James moved to National City and became the new art director for his former colleague, Cat Grant, at CatCo Worldwide Media. He is initially a potential love interest for Kara. Among his reasons for moving across the country are his breakup with his fiancée, Lucy Lane, and keeping an eye on the newly revealed Supergirl for Superman. While working at the Daily Planet, James received the Pulitzer Prize for taking the first photograph of Superman. In the second season, James becomes Guardian. In the fourth episode of season 5, James decides to leave National City to run his hometown newspaper. He returns in the series finale to assist the Superfriends in the final battle against Lex and Nyxly and attend Alex and Kelly's wedding.
Chyler Leigh as Alexandra "Alex" Danvers / Sentinel: Kara's human adoptive sister. She is a physician, bioengineer, scientist and government agent who serves as Hank Henshaw's right hand at the DEO. She also meets and befriends police detective Maggie Sawyer and begins to develop feelings for her, forcing Alex to confront her sexuality. Jordan Mazarati and Olivia Nikkanen portray a young Alex.
Jeremy Jordan as Winslow "Winn" Schott Jr. / Toyman (seasons 1–3; guest: seasons 5–6): A tech expert who worked alongside Kara at CatCo, he is Kara's best friend and serves as one of her allies, helping her develop her costume and aiding her in her adventures. Winn has unrequited feelings for Kara and is a rival with James for her affection.
David Harewood as J'onn J'onzz / Martian Manhunter: The head of the DEO who takes Hank Henshaw's likeness after Henshaw is killed in Peru while hunting J'onn. J'onn takes Henshaw's likeness to reform the DEO from within as well as to watch over Alex and Kara. The evolution of Henshaw was discussed during the filming of the pilot, with the executive producers jokingly saying that Harewood would be a good actor to play the Martian Manhunter in a potential television series, to which DC Comics' Geoff Johns asked why it could not be done in Supergirl. Harewood reflected that he had difficulty "find[ing] an angle to play Hank Henshaw" in the pilot, and became excited when he was told about the change to his character's backstory. Harewood also recurred in the series as the real Hank Henshaw, who became Cyborg Superman.
Calista Flockhart as Catherine J. "Cat" Grant (season 1; guest: seasons 2–3 & 6): The outwardly shallow and superficial, but inwardly sweet, founder of the media conglomerate CatCo Worldwide Media, who feels, since she "branded" Kara as "Supergirl", that she has proprietary custody over the new hero.
Chris Wood as Mon-El / Mike Matthews (seasons 2–3; guest: seasons 5–6): A prince from the planet Daxam with similar powers to Superman and Supergirl, Mon-El lands on Earth in the pod at the end of season one.
Floriana Lima as Margarita "Maggie" Sawyer (season 2; recurring: season 3): A detective for the National City Police Department who takes a special interest in the cases involving aliens and metahumans. The first openly gay character introduced, Maggie dates Alex Danvers, even becoming engaged. However, this is broken off. Lima became a recurring actress for the third season, departing in the season's fifth episode. Lima noted the role was only intended to last for one season.
Katie McGrath as Lena Kieran Luthor (seasons 3–6; recurring: season 2): The CEO of L-Corp (formerly known as Luthor Corp) and the younger paternal half-sister of Lex Luthor. Camille Marty portrays a young Lena.
Odette Annable as Samantha "Sam" Arias / Reign (season 3; guest: season 5): Another Kryptonian sent to Earth as an infant and single mother to her daughter Ruby. Samantha's villainous alternate personality, Reign, emerges in the middle of season 3, but she is unaware of it and her alter ego's actions.
Jesse Rath as Querl "Brainy" Dox / Brainiac 5 (seasons 4–6; recurring: season 3): A half-A.I., half-organic 12th-level intellect from the planet Colu and a member of the Legion of Super-Heroes in the 31st century.
Sam Witwer as Benjamin Lockwood / Agent Liberty (season 4; guest: season 5): The brilliant, ruthless, and terrifying founder and figurehead of Children of Liberty, a human-supremacist hate group that supports a human-first world order.
Nicole Maines as Nia Nal / Dreamer (seasons 4–6): A soulful young transgender woman with a fierce drive to protect others and the newest addition to the CatCo reporting team. The character is the first transgender superhero on television.
April Parker Jones as Colonel Lauren Haley (season 4): A hardline career military woman who lives and dies by the orders of her commanding officers. Dedicated to her country, she always acts in its best interest — even if it's not her own.
Azie Tesfai as Kelly Olsen (seasons 5–6; recurring: season 4): James's younger, no-nonsense sister, recently returned to the United States following a military tour overseas.
Andrea Brooks as Eve Teschmacher (season 5; recurring: seasons 2–4; guest: season 6): A former CatCo assistant who became part of Lena's research team at L-Corp before being revealed as a dastardly turncoat spy working for Lex Luthor.
Julie Gonzalo as Andrea Rojas / Acrata (seasons 5–6): A CEO of Obsidian Tech who is the new editor-in-chief of Catco Worldwide Media and an old friend of Lena Luthor.
Staz Nair as William Dey (seasons 5–6): A new star reporter at Catco Worldwide Media who is secretly remains under the London Times newspapers' employ and undercover to investigates Andrea Rojas, suspecting that she is a criminal.
LaMonica Garrett as Mar Novu / Monitor (season 5; guest: season 4): A multiversal being testing different Earths in the multiverse in preparation for an impending "crisis", providing the Book of Destiny to John Deegan, releasing J'onn J'onzz's brother, and retrieving the corpse of Lex Luthor. He made his first appearance in the Arrowverse crossover "Elseworlds".
Garrett also portrays Mobius / Anti-Monitor, the Monitor's polar opposite, an evil being dedicated to ending the multiverse.
Peta Sergeant as Nyxlygsptlnz "Nyxly" (season 6): A 5th Dimension Imp princess who Kara meets in the Phantom Zone, who desires revenge on her father for banishing her and killing her brother, and is willing to do whatever is necessary to get it.