Mxyzptlk, an imp with powers to manipulate reality, proposes marriage Kara, who refuses, making him take it as a challenge. Mon-El suggests killing Mxyzptlk, which she rejects. Mxyzptlk summons Parasite to attack National City before killing it in order to impress her, failing. Mon-El inadvertently reveals that another way to remove imps is by getting them to say or spell their names backwards. Later, Winn discovers a device in the DEO's collection that is connected to the fifth dimensional energy that Mxyzptlk draws power from. Mon-El attempts to use it to duel with Mxyzptlk to the death. Mxyzptlk eventually gains the upper hand and tries to kill Mon-El, only for Kara to arrive and agree to marry him. He later arrives at the Fortress of Solitude for his wedding, but Kara states that she will not marry him. Angered, he attacks her, but she stops the battle by locking the fortress down and activating the self-destruct sequence. Mxyzptlk begs for the code to stop the countdown but, after inputting the code, realizes that it spells his name backwards and is defeated. Mon-El and Kara develop romance. Meanwhile, Winn starts dating Lyra Strayd, an alien from Starhaven.

Lena testifies against Lillian; Kara encourages her to visit Lillian, who reveals that she is her husband's daughter from another woman. A package of synthetic kryptonite is sent to Corben. While testifying, he attacks the court and frees Lillian. A faked video is leaked showing Lena stealing the kryptonite, and she is arrested on suspicion of helping Lillian. Corben breaks her out. Kara remains as the only person to believe in Lena's innocence. Lillian takes Lena to a remote facility set up by Lex before his imprisonment and forces her to access a stockpile of alien weapons, several of which she takes. Kara arrives and intervenes. Winn determines that the synthetic kryptonite is becoming increasingly unstable and will soon explode, and Kara manages to save Lena before Corben self-destructs, while Lillian and Henshaw escape by helicopter. Lena is exonerated, but begins contemplating her relationship with her family, especially Lex. Kara and Mon-El, who ended his relationship with Teschmacher, confess their feelings for each other at her apartment when a man calling himself Mister Mxyzptlk arrives and declares his love for her.

J'onn starts following M'gann so as to protect her. Armek, her former mate, comes to Earth with orders to take her back to Mars for execution, and gives her two hours to surrender before he goes after her friends. Fearful, J'onn decides to bring her to the DEO for protection. The real M'gann shows up, revealing the other one to be Armek in disguise, forcing J'onn to put the DEO into lockdown. Assuming Winn's identity, Armek initiates a meltdown in the building's nuclear reactor, while another White Martian posing as Alex ambushes Kara. J'onn and M'gann free the real Winn and Alex and confront Armek, killing him with a metal pole. Winn fixes the reactor in time, and Alex helps Kara subdue the other Martian. Afterwards, M'gann informs J'onn that she intends to return to her home planet in order to reform her people. Encouraged by Alex, Kara tries to ask Mon out on a date, only to find that he already has a relationship with Eve.

Kara starts training Mon-El. Leslie is announced having broken out of imprisonment. Kara and Mon-El engage Livewire, who is revealed to be another woman, who attacks the pair with a male Livewire. Mon-El ignores Kara's instruction to protect the civilians in order to save her. The Guardian arrives and aids them. The Livewires escape; and Kara finds out about James' alter ego, scolding him and Winn. She also gets angry with Mon-El for prioritizing her over the others. The DEO learns that Leslie was actually abducted from incarceration. Winn locates her. James and Mon-El rush there to prove themselves. The duo is captured by the scientist, who has been draining Leslie's powers and giving them to his subjects. Kara arrives and saves them, freeing Leslie and dissuading her from killing the scientist, allowing her to escape in exchange. Kara rejects James' offer for cooperation in vigilantism. Mon-El confirms his feelings for her. Meanwhile, M'gann loses consciousness. J'onn agrees to bond with her. In a shared memory, he tells her that she is forgiven. She regains consciousness; and J'onn frees her. She reveals that the White Martians are searching for her.

Winn gets beaten aiding James, leading the former to believe he is not fit for field. Kara starts investigating a strange series of missing persons. The DEO tracks the kidnappings to a fake clinical trial, which is revealed to be run by aliens. Tracking them, Kara and Mon-El pass a portal and enter the planet Maaldoria, which is the center of slave trade. Realizing that they will not have their powers due to Maaldoria's red sun, the pair tracks the kidnappees to a fortress, where they intentionally get captured and are put in the same cell as the others. They learn that Roulette is involved in the trafficking. Meanwhile, J'onn reveals that the Maaldorian atmosphere is lethal to the Martians, making Alex lead the rescue team, convincing Winn to join her. Kara incites a riot; and the prisoners lock Roulette and her Maaldorian accomplice in the cell and escape. Reuniting with the DEO, they get to the portal and return to Earth. Winn accepts his potential while Mon-El, whom the Maaldorians intentionally allowed to leave, decides to become a superhero. An alien group is revealed to be searching for Mon-El. Maggie tells Alex about her knowledge of Kara's alter ego.

Cyborg Superman unleashes a virus in a bar, killing all aliens there except Mon-El, who is quarantined by DEO. Eliza, visiting for Thanksgiving, determines that the virus is Kryptonian. At the Fortress of Solitude, Kara learns that Henshaw was after "Medusa", a virus created by her father, Zor-El, to kill non-Kryptonian in case of alien invasion. At L-Corp, she stops Henshaw from getting the isotope required to disperse Medusa. Lena refuses to help when Kara reveals that Lillian is Cadmus' leader. Later, Lena willingly gives Lillian the isotope. Kara and J'onn confront the Luthors and Henshaw before Medusa is launched via rocket. J'onn fights Henshaw, becoming a White Martian, while Kara chases the rocket, which explodes and disperses Medusa. However, Lena has double-crossed Lillian and rendered the virus inert. Lillian is arrested but Henshaw escapes. Eliza cures Mon-El and uses Medusa to restore J'onn's Green Martian form. Alex comes out to Eliza, who supports her. Later, Maggie and Alex kiss after Maggie admits she does have feelings for Alex. An unknown alien race is searching for Mon-El. Barry Allen and Cisco Ramon arrive from another Earth to enlist Kara's help.

A new vigilante appears in National City and starts killing some of the criminals James secures. Mon-El makes an unsuccessful escape attempt. Lillian demands Kara to arrive at Cadmus by threatening him. Kara arrives and is overpowered by the real Hank, who is enhanced and called the "Cyborg Superman". Winn deduces that the vigilante targets the murderers who were exonerated. The former finds the next target, with James managing to defeat the serial killer, who is arrested. Lillian, whom Kara identifies, forces her to deplete her powers, giving the former the chance to take blood samples of her. Jeremiah saves Kara and Mon-El and helps them escape by staying behind. Kara finally approves the Guardian while Alex finds out about his true identity. Mon-El develops feelings for Kara. Cyborg Superman arrives at the Kryptonian base in the North Pole and uses Kara's blood to trick the system into recognizing him as her, demanding to know about the "Medusa" project. Meanwhile, J'onn begins having hallucinations and finds out about M'gann, whom he locks in the DEO. She warns him that the transfusion will turn him into a White Martian. Alex finally accepts Maggie as just a friend.

In Norway, a group of scientists led by Dr. Jones discover an abnormal dead wolf, which causes the mysterious murder of all the scientists except Jones, who is revealed to be infected by a parasite. The DEO finds out that Jones killed the other scientists. Kara gets angry with Mon-El when she finds out that he uses his powers to make money. The DEO predicts Jones' next target and Kara and J'onn attempt to stop him; but the latter drains their powers, becomes larger and stronger and escapes, leaving the pair weakened and unconscious. Alex convinces M'gann to donate blood in order to save J'onn. Jones attacks his target again; but Mon-El intervenes. With his suit ready, James arrives to fight Jones too, taking the alias "Guardian". Kara regains consciousness and attacks Jones, taking Plutonium 239, which he touches, causing him to be overloaded with energy and implode. James convinces Winn not to tell Kara about his alter ego. Mon-El is abducted by Cadmus. Meanwhile, Alex tells Kara about her feelings for Maggie. Kara encourages her to date Maggie, who reveals that she prefers just a friendship, upsetting Alex.

J'onn asks that Mon-El stay at the DEO until he is fully examined. An alien body is found, and the DEO track down the murderer, who is kidnapped by unknown armed men. Maggie and Alex track him down to a secret facility hosting people of high political and economical status run by a woman, later identified as Veronica Sinclair, also known as Roulette. The aliens are forced to duel, sometimes to the death. They spot M'gann as a contestant before Kara intervenes and is attacked by an alien called Draaga, who overpowers her and escapes. J'onn confronts M'gann, who says that she believes herself guilty of surviving the extinction of her species. Veronica abducts J'onn and M'gann. Using Lena, Kara finds the address, where J'onn and M'gann are forced to duel until J'onn convinces her to stop blaming herself and they refuse to continue. When they are attacked by Draaga, Kara arrives and defeats him thanks to Mon-El's advice, dissuading the other aliens from protecting Veronica, who is arrested but later released by orders from higher up. Alex asks Maggie to get a drink before Maggie's date arrives, while Kara decides to train Mon-El. M'gann secretly shapeshifts to reveal that she is a White Martian.

A group of robbers, led by Chet Miner, starts challenging Supergirl using alien guns. Cadmus demands the repealing of the Amnesty as a solution. Kara deduces that Cadmus is arming Miner's team. Lena holds a fundraiser, which is attacked by Miner and his men. She reveals to Winn that the fundraiser was a ruse for the robbers, and they activate a device that destroys the alien weapons, leading to the robbers' arrest. Miner and his team are killed by Cadmus before he can expose them. The Cadmus leader is revealed to be Lilian, Lena's mother. Meanwhile, Kara takes Mon-El to CatCo for work, but he continuously ignores her commands, leading to being fired. Alex convinces her to let him choose his own path. James starts operating as a vigilante. Winn finds out and initially blames him, but finally decides to help, intending to make a suit for him. Alex learns that Maggie has broken up with her girlfriend and offers her another date, with Maggie realising Alex is a lesbian, and Alex herself accepting the fact.