Supergirl is an American television series developed by Greg Berlanti, Ali Adler, and Andrew Kreisberg based on the characters created by Jerry Siegel and Joe Shuster in the Superman franchise and Al Plastino and Otto Binder's character Supergirl. The series stars Melissa Benoist in the titular role of Kara Zor-El / Kara Danvers / Supergirl, as well as Mehcad Brooks, Chyler Leigh, Jeremy Jordan, David Harewood and Calista Flockhart, with Katie McGrath, Chris Wood, Floriana Lima, Odette Annable, Jesse Rath, Sam Witwer, Nicole Maines, April Parker Jones, Azie Tesfai, Andrea Brooks, Julie Gonzalo, Staz Nair, LaMonica Garrett and Peta Sergeant joining in later seasons. In addition to original characters, several other characters from the DC Comics universe also appear throughout the series. For its first season, Supergirl aired on CBS, before moving to The CW for its second season.

The series follows Kryptonian refugee and Superman's biological cousin Kara Zor-El (Benoist), who, after hiding her powers on Earth for more than a decade, becomes National City's superhero as Supergirl, battles against extraterrestrial and otherworldly threats, criminal masterminds, being targeted by her cousin's rogues gallery, and encountering an emerging community of metahumans within her adoptive world and individuals from parallel universes. Supergirl also deals with the Earth populace's fears and hostility against extraterrestrials and other beings with superpowers, leading her into conflicts with industrialist Maxwell Lord (Peter Facinelli), Lucy Lane's (Jenna Dewan) father General Sam Lane (Glenn Morshower) and Project Cadmus. She is assisted by a few close friends and family who guard her secrets—most notably her cousin's longtime friend James Olsen (Brooks), her adopted sister Alex Danvers (Leigh), and the Martian survivor J'onn J'onzz (Harewood).

The following is a list of characters who have appeared in the television series. Many are named after (or based on) DC Comics characters.

Kara Zor-El / Kara Danvers / Supergirl (Melissa Benoist as an adult, seasons 1–6; Malina Weissman and Izabela Vidovic as a teenager) is a 24-year-old Kryptonian living in National City, who must embrace her powers after previously hiding them. When her pod crashed on Earth at a young age, she was found by her cousin Superman and was taken to live with his friend Jeremiah Danvers. She assists her adoptive sister, Alex Danvers, as part of the Department of Extranormal Operations (DEO). She discovers the truth that Jeremiah Danvers also worked for the DEO, so they would not take Kara. Alex's co-workers at the DEO help Kara to perfect her powers. Kara has a day job, working as Cat Grant's assistant at CatCo. Kara learns of the existence of metahumans and the multiverse when she befriends Barry Allen, aka the Flash, a superhero from a parallel Earth (Earth-1). 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". Claire Holt and Gemma Atkinson were considered for the role.

In season two, Kara deals with feuds between Earth's native populace and the extraterrestrial community, and struggles with romantic feelings for Daxamite prince Mon-El. She learns that Superman was formerly a member of the DEO, making her his successor within the organization. She becomes close with Lex Luthor's paternal half-sister Lena, and is targeted by Luthor's mother, Lilian, leader of Project Cadmus, an organization now dedicated to the exploitation and destruction of all aliens. Kara's adversaries include Mon-El's mother, Rhea, who wants to retrieve her son, the prince of Daxam, and invade Earth. Kara also becomes a visiting superhero to Earth-1 and a recurring ally of its heroes, including Barry's best friend, Oliver Queen, the vigilante archer Green Arrow.

In season three, Kara deals with the threat of Selena and the Worldkillers, including a new character, Samantha "Sam" Arias/Reign, another refugee from Krypton who is at first unaware of her origins and of her evil persona. Eventually Sam and Reign are physically separated, and Sam killed Reign at the cost of her own life and others'. Kara travels back in time to save Sam and prevent the sacrifice of Mon-El and of Kara's mother, Alura, who has survived Krypton. Kara takes the Harun-El (Black Kryptonite) with Sam and Reign into the Fountain of Lilith, taking down Reign. Unbeknownst to her, another Kara appears in the border of Siberia.

In season four, Kara deals with a new wave of anti-alien sentiment from the public, both as Supergirl and as a CatCo reporter. The hostility is secretly orchestrated by Lex Luthor. During the fight at Shelly Island, Supergirl fights against Lex Luthor using a special lead suit. Red Daughter sacrifices her life to give Supergirl the opportunity to defeat Lex Luthor.

In season five, Kara finds that CatCo is bought out by Andrea Rojas and she also contends with Leviathan. During the "Arrowverse", Supergirl, Superman, and Lois Lane work with their Earth-1 allies in their attempt to save the people of Earth-38 and becomes one of the Paragons at the cost of Oliver Queen. When Anti-Monitor destroys most of the Multiverse, Kara and the rest of the Paragons fight Anti-Monitor and the Shadow Demons. Oliver's second sacrifice as Spectre resulted in the creation of Earth-Prime where she finds that Lex Luthor was never a bad guy and LuthorCorp owns the DEO After finding that her Earth merged with Flash's Earth and Black Lightning's unnamed Earth, Supergirl and her allies fight the Anti-Monitor again. Afterwards, Supergirl contends with the plots of Lex Luthor and Leviathan.