Kate (Mary Elizabeth Winstead) is an assassin and expert sniper who eliminates targets chosen by her trusted mentor and handler, Varrick (Woody Harrelson). After she was left orphaned as a child, Varrick raised her as a father figure, giving her extensive training in weapons and combat and eventually inducting her into his private team of wet work specialists. Kate has not missed a target for Varrick in 12 years.
Kate is in Osaka to kill an officer of a powerful Yakuza syndicate, but Kate resists taking the shot because a child has unexpectedly accompanied him. She ultimately shoots the target at Varrick's insistence as he says that letting the target go would mean wasting seven years of hard work in locating him. The little girl accompanying the target was abandoned, left alone, defenseless and vulnerable as everyone near the target ran away as he was shot dead.
While Kate's assignment is a success, this breach of her personal code to not kill in the presence of children leaves her in emotional turmoil.
10 months later, she tells Varrick that she will do one final mission and then retire so she can start a new life.
Before the final mission, Kate meets a charismatic stranger, Stephen (Michiel Huisman), at her hotel's bar. The pair share a bottle of wine and have sex in her room. Kate then leaves when it is time to complete her mission, and leaves money on the dresser for Stephen.
Later, while preparing her sniper's nest, she starts getting symptoms of dizziness that cause her to miss the shot at her target. Kate's symptoms get worse as she tries to steal a car to get away and even vomits along the way. The bodyguards of the target were on the streets looking for the sniper and are instantly suspicious of the western woman trying to get away in a car in a hurry.
Kate realizes that Stephen poisoned her and crashes her car after she was chased by the bodyguards of her target. She wakes up in a hospital a day later to learn that she has acute radiation poisoning caused by Polonium-204 and only twenty-four hours to live. Kate remembers that Stephen never drank his wine.
She steals a gun from the police officer guarding her room and forces a doctor at gunpoint to create 5 injections of stimulant doses for her and sets out to exact revenge on whoever poisoned her.
Kate tracks down Stephen as she had looked at Stephen's ID card after they had had sex and memorized his address. Stephen was with his girlfriend, and Kate learns that they were strong-armed into poisoning her by Sato, a Yakuza affiliated with the Kijima crime family. Kate spares Stephen when his girlfriend begs that Stephen only did this as Sato promised to free Stephen from his debt if he did this. She says that she and Stephen can finally start their life now.
Kate meets Varrick, who expresses sympathy for her being poisoned. Varrick tells Kate that her last mark was Kijima (Jun Kunimura). Her mark at the previous hit in Osaka was Kijima's younger brother Kentaro.
Kate finds Sato at a luxury restaurant and kills him along with dozens of armed Yakuza. Desperate for information about the reclusive, well-guarded boss Kijima, who she thinks might be behind the poisoning, the last surviving bodyguard of Sato tells her that Ani would know about Kijima's location. Kate kidnaps Ani (Miku Martineau), Kijima's niece. Kate realizes that Ani is the girl who saw her father die during the Osaka mission.
Kate initially only wants to use Ani as bait to lure Kijima out into the open. She gets Ani to call Kijima's top advisor Renji (Tadanobu Asano) and asks him to tell Kijima to meet at a public place within an hour. Renji had sent his entire army to kill Kate and Ani. Kate kills off Renji's men in a brutal assault. Kate had bound Ani inside a public toilet, but she manages to escape and encounters Renji top man Shinzo (Kazuya Tanabe), who was given orders to kill Ani. Ani realizes that Shinzo was sent to kill her.
Kate decides to become her protector upon learning that Ani's family wants to kill her as part of an internal power struggle, led by Kijima's corrupt advisor, Renji. Kate kills Shinzo and the remaining Yakuza, loyal to Renji.
Ani helps Kate by telling her that Renji is likely to be with his boyfriend Jojima (Miyavi) at an expensive penthouse apartment. Ani helps Kate infiltrate the penthouse where she engages in a brutal fight with Jojima, before Ani manages to load a gun and shoot him dead. Ani finds Jojima's phone which has a cell tracker on Renji. Kate and Ani attack Renji's car in the middle of a deserted road, kill his guards and isolate him. Renji gives clues to Kijima's location and Ani figures it out. Kate lets Renji live. Kate calls Varrick and tells him Kijima's location and that she is going to finish it.
Kate meets Kijima where he sits unprotected, in his old family home, which nobody knows about. She uncovers more clues about the Osaka mission and realizes that her trust in Varrick may be misplaced after Kijima reveals that Renji made a deal with Varrick to incorporate his team into the syndicate in exchange for killing Kijima and all of his blood relatives.
Kate emerges from the meeting only to find Varrick next to Ani. Varrick has told her that Kate killed her family. Ani is distraught and shoots Kate in the face and leaves with Varrick. Kate survives the shot.
Kijima, aware that Kate is close to death, provides her with a small army of his men to assault Renji's headquarters. Kijima provides another stimulant shot, which will last one hour.
After a fierce gunfight, most of Renji and Varrick's men are killed, and Kijima personally beheads Renji for his betrayal. Kate locates Varrick, who is holding Ani at gunpoint. The two have a fast draw and Varrick is fatally shot in the stomach. Ani then helps Kate walk outside to the roof, where Kate sheds a single tear as she succumbs to her poisoning.
