The film opens with a montage showing a group of bald children receiving tattoos of bar codes and being instructed to use of firearms & martial arts.

Interpol agent Mike Whittier discovers Agent 47 in his study, where the two talk briefly. The scene flashes back 3 months, as 47 is completing a hit in Niger. He receives a communication from his Agency contact, Diana, and is told he is to kill his next target, Russian President Mikhail Belicoff, publicly.

Agent 47 kills Belicoff using a sniper rifle to achieve a head shot from over 4 km away. However, when 47 is in the train station ready to leave, he's told there's a witness–Nika Boronina–whom he must kill. Confronting Nika on a street, he realizes she's never seen him before and decides not to kill her. Additionally, Belicoff's death was covered up, being portrayed in the media as a grazing wound. Agent 47 then escapes a failed assassination attempt.

Agent 47 confronts Diana about who would want Nika dead when she wasn't a witness and why Belicoff is still being portrayed as alive. Outside, Mike Whittier and his partner have been tipped off that 47 is in the hotel. They encounter the FSB, led by Yuri Marklov, who sends in an emergency response team to capture 47. Diana calls 47 directly, informing him that it was Belicoff himself who ordered the hit. The troops attack and a hotel battle ensues. Agent 47 successfully escapes. However, the Agency he works for has dispatched assassins to kill him for failing his mission.

Agent 47 kidnaps Nika, who was about to be killed by her driver, and questions her. She suggests 47 may have killed one of Belicoff's doubles, but 47 denies that possibility. The two try to leave by train, but are intercepted by the Agency's assassins. Agent 47 defeats four of them including the assassin who tried to assassinate him earlier. He also defeats Mike Whittier who pursued, and escapes with Nika.

Agent 47 arranges a meeting with Agent Smith, later to be revealed as a member of the CIA. Smith reveals to Agent 47 that Belicoff's opponents ordered the hit on the real Belicoff and replaced him with a double who is loyal to them. Agent 47 then offers Smith a deal: if Smith helps him during some unrevealed time in the future, 47 will kill Belicoff's brother, Udre, a slave trafficker, and arms dealer. Smith accepts the deal. Agent 47 and Nika travel to Turkey and after kidnapping and impersonating arms-dealer Mr. Price, he kills Udre in an ensuing fire fight. Udre is shot in the head.

The death of Udre was a set-up designed to draw into the open the fake Belicoff who, working with Yuri and an unseen cabal, is part of a plot to have a puppet leader in control of Russia. Agent 47 kidnaps Yuri and forces him to have his own FSB agents try to shoot Belicoff as he delivers a eulogy for Udre. Agent 47, disguised as a soldier, manages to kill all of Belicoff's guards and takes him into the archbishop's chamber in the church, and after having a small conversation with Belicoff, he kills him by shooting him point blank in the head. He then allows himself to be taken into custody by Interpol and Mike Whittier, being transported in a Mercedes-Benz G500. However, Agent Smith intercedes at the last minute with a fleet of black Audi Q7's, allowing 47 to escape.

There is a flash forward to the conversation between agent Whittier and 47 occurring at Whitter's house. After wrapping up their conversation, 47 reveals the body of Mr. Price, shaved and dressed to look like 47. They make a deal in which Whitter would go along with 47's plan, admitting that the body in his home is the real 47. As 47 leaves, he turns to Whittier and says that he hopes to never see Whittier again.

The scene then changes to Nika, who is shown picking up an envelope from an undisclosed sender. Inside it, there were papers and a message saying that she now owns a vineyard (she had told 47 of her childhood dream of having one). Meanwhile, 47 is watching her from afar, through the scope of his sniper rifle. He then looks at the corpse of another hitman, lying close to him, and says "I told you to leave her alone. You should have listened." He then turns back, and walks away.

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