Supergirl's enemies can be classified in several main categories:
- Lesla-Lar: Supergirl's first serious enemy, Lesla-Lar was a Kandorian scientist envious of Supergirl. She impersonated the Maid of Might, planning to use Lex Luthor's assistance to kill Superman and then killing Luthor and taker over the world. Later she attempted to possess Supergirl's body. Valuing cunning and intelligence to brute strength, she struck her targets indirectly and through minions, and avoided direct confrontation as much as possible.
- Xenon: An enigmatic being that was imprisoned by a Supergirl in a mystical prison, Xenon extended his hatred to all Supergirls, not only the one jailed him, and used his powers to bring them in his domain and kill them. He was powerful enough to destroy an Earth-One Kryptonian, and he was willing to see the Multiverse destroyed as long as he had his way.
- Worldkiller-1: A parasitic sentient organism, Worldkiller-1 follows an extreme "Survival of the Fittest" code, decimating alien races in the belief that the survivors will become stronger and better.
- Atrocitus: Atrocitus became an enemy of Supergirl when she allied with Guy Gardener during the Red Lantern civil war.
- Brainiac: As a Kryptonian, Supergirl hates Brainiac for his part in Kryton's destruction and bottling up Kandor. She also hates him for turning her father into the Cyborg Superman.
- Kryptonite Man: Last scion of a Kryptonian humanoid race, Kryptonite Man has the powers of an average Kryptonian plus a body that gives off K-radiation permanently.
- Queen Rhea: In an alternate dimension, Supergirl dated the Crown Prince of Daxam. His mother Queen Rhea didn't take this well, and set out to invade Earth and get rid of Supergirl.
- Positive Man: Positive Man was once a mad alien scientist that blew his planet up as building a doomsday weapon. The explosion turned him into a massive, intangible energy creature blinded by hatred and jealousy of all living beings. Positive Man wandered over the cosmos, obliterating inhabited worlds until Supergirl put a permanent stop to him.
- Lady Styx: In a possible future, Lady Styx killed most of Justice Leaguers and conquered Earth. An incarnation of Supergirl led the Justice League against that powerful, ancient entity.
- Dominators: In an alternate dimension, Supergirl aided in fighting back the Dominators' invasion of earth.
- Diasporans: A race of warriors that decimated whole alien races in hopes of strengthening the survivors.
- Worldkillers: The Worldkillers were a group of aliens enhanced genetically and programmed to conquer worlds by a group of Kryptonian scientists, including Zor-el.
- Fatal Five: A team made up of villains who intend to prevent their future defeats at Supergirl's hands by defeating her in the past.
- Emerald Empress: After seeing a vision of her defeat at the hands of Supergirl, she now seeks to kill her to prevent the vision from coming true.
- Selena: A villain who escaped the limbo dimension. She officially became Supergirl's enemy when she joined the Fatal Five.
- Indigo: A version of Brainiac. Like the original, she hates all kryptonians and seeks to kill her. She joined the Fatal Five to achieve this goal.
- Magog: A man who blames meta-humans for what happened to his sister.
- Solomon Grundy Clone:
- The Gang: A group of friends raised in poverty that worked out and became villains to make money quick and get out of the slums.
- Bizarro Supergirl: Bizarro-Girl was Supergirl's Bizarro backwards counterpart. She disturbed Supergirl greatly because Supergirl realized she wasn't her opposite but her mirror.
- Dark Supergirl: Dark Supergirl was born when Lex Luthor exposed Supergirl to a shard of Black Kryptonite and was the embodiment of Supergirl's worst side, specifically her self-loathing and "survivor guilt".
- Nightflame: Nightflame was a sword-wielding sorceress that embodied Supergirl's death wish and looked to steal her body.
- Satan Girl: Similar to Dark Supergirl, Satan Girl was a double created by exposure to Red Kryptonite. Satan Girl siphoned life-force off the female Legionnaires to keep herself alive and tried to kill Supergirl. Later incarnations include an ancient demoness and an alien death goddess.
- Galatea: A clone created by Professor Hamilton in case Superman went rogue, Galatea broke free from Cadmus and set out to hunt down those who knew about her and attempted to kill Supergirl several times.
- Reactron: Benjamin Krull is a violent, psychopathic, sleazy, egotistical, mass-murdering, bullying thug who acts cocky and grinning as long as he thinks he has the upper hand. Holding an irrational grudge against Supergirl because she beat him down once he attempted to kill her over and again. He failed, but he managed to murder her father -to her face-, her mother and her whole race (but her cousin).
- Superwoman: General Sam Lane's elder daughter, Superwoman pretended to be a friend when she first approached Supergirl before revealing she was working for Lane and with Reactron. Superwoman attempted to frame Supergirl for a murder she committed and kill her several times, and was abettor in the Kryptonian genocide.
- Starfire: Starfire was a mob leader looking to take over the world. Supergirl clashed with her when Starfire nullified her powers as a first step to get rid of the super-hero community.
- Nasthalthia 'Nasty' Luthor: Lex Luthor's niece spent years trying to discover Supergirl's secret identity and then endeavouring to out her or get her fired.
- Lena Thorul: Although Lex's little sister is often a friend of or ally to Supergirl in her civilian or hero identity, a Lena's counterpart had been brainwashed by her brother into hating all aliens, including the Girl of Steel.
- Black Banshee: Supergirl despises Black Banshee for the trauma he put Siobath through and his actions towards her.
- Simon Tycho: A corrupt businessmen that kidnapped supergirl when she had just arrived on the planet to make profit from her and her pod's technology.
- Felix Faust: Faust once took over Supergirl's body and used her to attack Themiscara.
- Alphonse Luzano: Petty amoral scientist.
- Dax: Overlord of an alternate dimension.
- Rebel: Minor crime boss who tried to set shop in Leesburg only to run into two Supergirls. He tried to confront them again after a being known as the Fatalist turned him into a super-powerful half-golem.
- Derek Ames Starfire's underlying, tricked Supergirl into taking an experimental depowering pill.
- Shyla Kor-Onn: An ex-Phantom Zoner, Shyla drained the life-force of several students of New Athens Experimental School and tried to steal Supergirl's powers. Later she framed Supergirl for a crime she didn't commit to get her sent to the Zone.
Supergirl has made many enemies during her career, partially due to her constant moving from a city to another. She has also made many enemies in outer space. Despite this, she has never had a definitive arch-enemy, though recently, Reign and Emerald Empress have taken on this role.
Equipment: None known.
Transportation: None known.
Weapons: None known.
- No special notes.
- No trivia.