We start on a rainy street in London, where Interpol officer Mike Whittier (Dougray Scott) is just arriving home after a continually frustrating case. He goes inside and turns on a couple lights and fixes himself a drink. The lights fail, and he heads for his home office to try and fix it. He enters the office and someone says, "Nice family," commenting on the pictures. Whittier turn and sees the ruthless hitman known only to those who know as Agent 47 (Timothy Olyphant, who far surpasses expectations). 47 assures Whittier that if he wanted to kill him than he would have done it that morning as he left for work, but instead he just wants to talk. He warns Whittier that depending on his answers he can either die or keep living. He then proceeds to ask Whittier if he thinks he (Whittier) is a good man, and what can make a good man kill....
We jump back in time three months, to the Niger River Valley. A group of African gangsters are bringing in an old man -- presumably someone who didn't deliver -- to see their warlord. The man starts weeping, and the warlord notices something on his chest and asks one of the toughs about it. When the tough says that this is how he was delivered, we zoom out and see Agent 47 watching from a distant rooftop. He looks at a remote in his hand and presses a button, and the man, the druglord, and everyone around them blow sky-high. Not long after, we see Whittier and his partner, Jenkins (Michael Offei) arguing with the Nigerian police about 47 and how they need cooperation. We also find out that Whittier has been chasing 47 for three years and that he has connected 47 to over one hundred kills across the globe. Meanwhile, we see 47 in a bar in St. Petersburg where a woman named June is unsuccessfully trying to hook up with him. He bids her good night and heads back for his room, pausing only to put something in a nearby ice chest. After going into his room and setting a door bomb in case of unwanted guests, 47 calls his agency contact Diana on the computer. She tells him about the next job -- Mikhail Belicoff, president of Russia (Ulrich Thomsen). Diana advises him that the person who hired them wants to make it public, and 47 gets a look on his face but still agrees to the mission.
The next day, Belikoff is giving a speech regarding the upcoming election when a sniper bullet of 47's suddenly takes him out. 47 stows the sniper rifle in his case and runs off, leaving just before the case blows up, eliminating any evidence. That night though, he finds out two things -- Belikoff is still alive (meaning he won't get paid) and there was a witness, a little Russian girl. 47 is furious (as much as he ever gets) and tells Diana that if he is being set up by her, he will kill everyone in the agency. He then demands to know who ordered the hit and instead of going over the computer, Diana actually calls him and says it was.....Belikoff? Things go from bad to worse though when a team led by Whittier shows up to bag 47. However, he makes quick work out of all of them with two pistols he had stowed in the ice chest earlier before jumping out the window and into the Neva River. During the rundown, Whittier chews out the general who told the troops to go ahead, but is stopped by the arrival of FSB agent Yuri Marklow (Robert Knepper), who isn't too happy with Interpol doing a manhunt without their authorization. Also, when sifting through the evidence, Mike and Jenkins find a case of 47s containing a few small bottles with the symbol for the organization on them and a cross, which they eventually find has a Latin inscription of "Open the door to the lord and he shall guide your path forever" (or something like that) on it.
Elsewhere, 47 has acquired a new suit (his regular suit from the games plus a snazzy black trenchcoat) and is heading to track down the witness, Nika Boronina (Olga Kurylenko). He finds her in a fancy hotel and after tricking his way in with some flowers he claims are from Belikoff (she's his whore, basically), he takes her somewhere damp and dirty and eventually she reveals that Belikoff used doubles, and that's how he's still alive -- it was a double that 47 killed. For a moment 47 almost kills her, but then he decides not to and tells her that the person he killed to get close to her was going to kill her, and that he was working for Belikoff, which means she's safer with 47. The pair move to get out of the city, with 47 solving the transportation problem by always throwing Nika in the trunk. They head for a train station, but Whittier and the rest are already there. Unbeknownst to them, though, is the presence of another Hitman. 47 notices him though, and after stowing Niki somewhere that isn't a trunk, he steals a uniform from a passing soccer/football team member and makes sure he is seen by the hitter. After a chase through the back paths of the station, the two eventually confront each other and face off. Both are equally skilled, but 47 is just a little quicker and manages to pin the guy down. After asking why they're after him and being told it's a hit on him, he kills the guy just when Niki pops up, having disobeyed 47's order to stay. As if that's not enough, 47 hears someone else. He investigates and comes face to face to face with three more hitmen. They all pull guns on each other, then smile and pull swords instead. Two of them go down pretty quick, but the last one is able to hold out until they're back on the tracks and 47 is choking him to death. That accomplished, the two make for the exit when Whittier and Jenkins show up. After putting Jenkins out (but not down), 47 is about to kill Mike when Nika says, "Don't", which 47 reluctantly agrees to. They finally leave, and next we see our Interpol boys getting patched up and told by Yuri (essentially) "Cooperate with us or get out of our country." Mike opts for option three -- telling Yuri off and planting a bug on him.
A little while later, Nika and 47 are hiding out in the mountains and not enjoying each other's company. While there, 47 is working on finding the next step in the trail. For that, he arranges a meeting with Agent Smith Jamison, a CIA contact of his. Using Nika, he gets the name of a guy connected to Belikoff's arms-dealing brother Udre (Henry Ian Cusick), a Mr. Price. 47 also tells Smith that he'll need a favor from him, but we don't see/hear what the favor is. The two head into Italy and start to warm up each other, with Nika mentioning how when she was a little girl she always wanted to have her own vineyard in France to grow wine in. 47 just nods and soon, the pair are in an Italian-looking city (don't remember where) and he is deciding to be nice to her, taking her shopping for a new dress and even getting them reservations at a rather nice restaurant that our Mr. Price just happens to frequent (why, that's a coincidence!). After some sneaking around (including a shot from above and behind him that could come right from the second game), 47 comes back out and tells Nika that they have dinner reservations at eight. Meanwhile, we check back in with Whittier and Jenkins, who are busy listening in on Yuri. They hear him make a phone call to someone after sending other people out of his office, and from what they can hear they realize he's talking to Belikoff. Before they can get more, two cars drive up saying that they are to escort the two of them to the airport and out of the country, which Mike and Jenkins reluctantly comply with.
That night, 47 and Nika are out dining, and for a wonder Nika is behaving herself. As a waiter passes destined for Price (who 47 has a clear view of), 47 grabs the drink and slips something into it without anyone noticing. He and Nika make some amusing small talk while she works on the wine when suddenly Price is violently sick. He heads to the bathroom and after a couple minutes, 47 follows, telling her to get the check, since they'll be leaving soon. He goes into the bathroom and gets patted down, but they don't find anything. Inside, Price is just coming out and 47 goes into the stall. He pulls out a silenced pistol from the tank and dispatches the guard and knocks Price out with a little needle sedative thing. He yells for help and the other guards come in and get killed. Not long after, he and Nika head back to the hotel room where she drunkenly tries to have sex with him, and he manages to knock her out with the needle thing (though I doubt it was really necessary). A little later, we see him arriving with Price's money at Udre's club/hangout. Things are going well at first, but someone soon whispers in Udre's ear, "That's not Price." The mood shifts and (more) guns are drawn, but 47 manages to take out everyone but Udre, who he says he wants to use to deliver a message to Belikoff. A shaking Udre asks what it is, and 47 raises his pistol and shoots him in the head.
Some time after that, on a train near the Russia/Turkey border. 47 tells Nika that he has to leave her, and gives her instructions to get off at the next stop and stay with the crowd, and that one day he'll find her (not romantically I think, but what the hell). Before he leaves, she finally asks his name, and he tells her that where he was raised they got numbers instead of names and gives her his. They go their separate ways and the next scene is in Russia, where Mike has just arrived back, although under extreme supervision. Meanwhile, we see Yuri meeting with the real Belikoff in a morgue and Belikoff admits that he is tired of hiding behind doubles, although it is worth it just to stay in office and be re-elected. That night, we see Yuri working late when he is suddenly captured by 47, who throws him in a tub surrounded by timers designed to go off at a specific time tomorrow, during Udre's funeral. When they do, about three thousand volts will be pumped into the water, frying Yuri. Before he leaves, 47 plops a rubber duck in the tub and a walkie-talkie in Yuri's hand and warns Yuri that no one will hear him scream for help from where he is. That done, he heads for the funeral.
At the church, we see many troops all over the place, with Mike moving among them. Inside, Belikoff is giving a eulogy for his brother as Yuri watches on TV and screams into the walkie for help. The seconds count down, the timers go off, 47 (hidden on a second floor balcony) fires a bullet at Belikoff, and....the bullet hits a specially installed glass shield. Belikoff is removed and we see 47 take off after him and Mike go in after 47. A cadre of troops are escorting Belikoff out when one of them opens fire on the others and takes Belikoff to a small chamber nearby. Outside, Mike is being told that they can't find Belikoff or 47 when he suddenly remembers the cross, which a bishop tells him is the key to the archbishops quarters, in the tallest tower. Inside the room, 47 is confronting Belikoff. The two engage in a rather calm discussion considering, and Belikoff offers 47 even more money to just walk away and he will call the whole thing off, clearing 47's name and letting him go back to his life. Instead, 47 just shoots him in the head and calmly waits for Mike and everyone else to show up and arrest him. They load him into a car and are taking him to the airport when suddenly a bunch of Homeland Security and CIA guys pull up, led by Agent Smith. They say that they want to talk to Mike about him being suspected of terrorism, but Mike points out that they're busy transporting a dangerous fugitive to Interpol HQ. Smith calmly asks, "What prisoner?" and we see that 47 has escaped once again. Mike looks around in frustration and Smith puts on his very best "oops" face, and everybody heads off. As they do, Smith glances a this cell phone and sees that he has received a text message. He looks at it and it says simply, "Now we're even." He smiles and closes the phone.
Back in London, a frustrated Mike is arriving home when he finds all the lights out and 47 waiting for him. They talk, and Mike answers the question of a good man killing by saying that he loves his family, and he will do anything to keep them safe, including killing. 47 nods and points to the floor, where one of the dead Hitmen from earlier is lying. 47 tells Mike that the shots were fired from the gun he keeps in the upstairs closet, and that if he keeps his office door closed for the next five hours until the kids leave for school and the wife leaves for work, there's no need for them to find out anything or be exposed to any of this. He turns to leave and then pauses and says, "Oh, and Agent Whittier....I really hope we don't ever see each other again."
Some time after all this, we see Nika picking up her mail and going for a walk in.....somewhere. As she goes through, she notices something from a real estate agency. Curious, she opens it and finds that she is now the owner of a moderate-sized vineyard in France. She looks around hoping to catch a glimpse of 47, but sees no one. A couple rooftops away and fifty feet above her though, we see 47 looking at her through a sniper scope. He looks at the dead body of another hitter lying at his feet, smiles grimly, and says, "I told you to leave her alone. You should have listened."
*CUT TO THE CHASE*
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Agent 47 is hired to kill the Russian President, Belicoff. It appears that the hit is a success but the President turns out to be alive.
What happened was the President himself hired Agent 47 to kill him, but it turns out it was a "double" that was killed instead. Agent 47 finds himself being hunted by Interpol and his own agency. He is on the run with Nika who was the prostitute of the President's brother.
At the end Agent 47 kills Belicoff in the church during his brother's funeral and agent Whittier (Dougray Scott) from Interpol arrests him.
Their vehicles are stopped by "CIA" agents that give Agent 47 a chance to slip away. It is never known if they were real CIA agents are just posing as them. At the end Agent 47 visits agent Whittier and leaves him a body with a shaved head and barcode on the back of his neck to tell his superiors that he caught him breaking in.