After positive fan reaction to Super-Girl, the first recurring and most familiar version of Supergirl, Kara Zor-El, debuted in 1959. Kara Zor-El first appeared in Action Comics #252 (May 1959) written by Otto Binder who also created Mary Marvel, Captain Marvel's sister and female spin-off. Like Supergirl, Mary Marvel was a teen-age female version of an adult male super-hero, wearing a costume that was identical to the older character other than substituting a short skirt for tights. Binder also created Miss America, a super-heroine who shared little other than the name with her sometimes co-star Captain America.

Kara Zor-El is the last survivor of Argo City of the planet Krypton, which had survived the explosion of the planet and had drifted through space. When the inhabitants of the colony are slain by Kryptonite, Kara is sent to Earth by her father Zor-El to be raised by her cousin Kal-El, known as Superman. Fearing that she might not be recognized by Superman, Kara's parents provide a costume based on the Man of Steel's own.

On Earth, Kara acquires super-powers identical to Superman's and adopts the secret identity of Linda Lee, an orphan at Midvale Orphanage. She conceals her blonde hair beneath a brunette wig and functions as Supergirl only in secret, at Superman's request, until she can gain (in his opinion) sufficient control of her powers. After being adopted by Fred and Edna Danvers, Superman decides his cousin is ready to begin operating openly as Supergirl.

In her secret identity, Linda attends Midvale High School as Linda Lee Danvers. In later years, after graduating from Stanhope College, she changes careers several times, holding jobs in student counseling, news reporting, and acting in a TV soap opera. She also attends college in Chicago. Kara has many boyfriends, including Richard (Dick) Malverne, Jerro the merboy from Atlantis, and member of the Legion of Super-Heroes, Brainiac 5. She does, however, shun serious commitments, putting her super-career first.

Supergirl's secret identity is a closely held secret and is known only to Superman, her foster parents, and the Legion of Super-Heroes, of which she serves as a member for a time. Like all Kryptonians, Supergirl is vulnerable to kryptonite. Streaky, Linda Danvers' orange cat, acquires temporary super-powers as a result of its exposure to "X-Kryptonite". Comet the Superhorse, a former centaur, is Supergirl's equine companion.

One way DC demonstrated the epic nature of its 12-issue limited series Crisis on Infinite Earths (April 1985-March 1986) was through the deaths of important characters. In issue #7 (October 1985), Supergirl bravely sacrifices her life to save her cousin and the multiverse from destruction. When Superman continuity rebooted after the Crisis on Infinite Earths, DC editorial felt that Superman should be the sole survivor of Krypton, resulting in Kara being removed from continuity. Unlike a number of other characters who are shown dying in the Crisis, no one remembers Kara dying or even ever having existed.

After the events of Infinite Crisis, many historical events from the Multiverse are now being remembered. Donna Troy, after her rebirth and inheritance of Harbinger's Orb, has recalled the original Kara Zor-El and her sacrifice to save the Universe.