The film picks up where Casino Royale left off as Bond is driving from Lake Como to Siena, Italy, with the captured Mr. White in the boot of his car, when he is attacked by chasing henchmen. After evading his pursuers, Bond, along with two agents and M, interrogate White at a secret safe house regarding his organisation, Quantum. M's trusted bodyguard Craig Mitchell betrays M, shooting a colleague and allowing White to escape. Bond chases Mitchell across Siena and kills him. Through forensic investigations involving tracked banknotes, Bond then heads to Haiti to find Mitchell's contact, Edmund Slate. Bond kills Slate, who was set to meet with Camille. Bond instead meets Camille, who believes that the man she is meeting is a geologist when in fact Slate was set to kill her at the behest of her partner, Dominic Greene. Bond is ejected from Camille's car and pursues her by motorbike. He sees her meeting with Greene, a ruthless businessman and chairman of Greene Planet, who is also a member of Quantum. Greene is helping General Medrano – who murdered Camille's family – to stage a coup d'état in Bolivia in exchange for a seemingly barren piece of desert land.
Greene introduces Camille to Medrano as a 'sweetner' for their deal and has her escorted away on Medrano's boat. Bond commandeers his own boat to rescue her (though she is unwilling) and leaves her in local care. Bond then tracks Greene, through the cellphone of Greene's henchman Elvis, to a private jet, which flies to Bregenz, Austria. Greene is accompanied on the flight by the CIA's Felix Leiter and Gregg Beam, who are brokering a deal to make the impending coup benefit America. Bond then follows Greene in Austria to a performance of Tosca at Lake Constance, which is being used as a clandestine site for members of Quantum to plan the coup, each member communicating through special earpieces concealed in gift bags. Bond himself obtains an earpiece and disrupts the meeting. He then sends MI6 cellphone photos of various Quantum members as they flee the arena. As Greene abruptly departs from the opera, he is intercepted by Bond and a gun fight ensues in a restaurant. Bond confronts a bodyguard, who has links to an advisor of the British Prime Minister, on a rooftop, but the ensuing struggle causes him to fall on the hood of Greene's vehicle. Greene apparently does not recognize him and has him killed.
Believing Bond killed yet another potentially vital source of information, M has 007's passports and credit cards revoked. Bond is still able to travel to Italy by boat, where he reunites with his old ally René Mathis, who now lives in a hilltop villa awarded to him by MI6 as compensation. Both immediately relocate their efforts to La Paz, Bolivia. They are greeted by Strawberry Fields, an MI6 field operative from the local British Consulate. Although she explains Bond must return to the UK on the next available flight, he disobeys and seduces her in their hotel suite. That night, they attend a fund raiser being held by Greene, where Camille reappears. The Bolivian police attempt to set up Bond by putting a beaten Mathis in his car boot. As Bond picks Mathis up from the boot, the policemen open fire and fatally injure Mathis. Bond disarms and kills the policemen and comforts the dying Mathis, who asks Bond to forgive Vesper Lynd, and forgive himself for what happened to her. Bond then places Mathis' body in a dumpster and empties his wallet.
Bond and Camille then drive to the location of Greene's intended land acquisition, surveying the area in a Douglas DC-3 propeller plane. They are intercepted by a chopper and a fighter plane sent by Medrano and subsequently shot down. Before crashing, both Bond and Camille jump from the crippled plane and then freefall/parachute into a sink hole. There, the duo discover Greene is not interested in oil, but has been blockading supplies of fresh water, hidden in underground rivers. After this revelation, they return to La Paz, where Bond meets M and discovers Quantum murdered Fields by symbolically drowning her in oil. M orders Bond to disarm and end his activities in Bolivia, but he escapes by overpowering several MI6 operatives accompanying him in a lift. After this escape Bond encounters and speaks to M, stating he is not finished with his operation. Bond then meets his CIA ally Felix Leiter at a local bar.
Leiter informs Bond of where Greene is set to complete his deal with Medrano. Bond and Camille thus go to an eco-hotel powered by hydrogen fuel cells, located in the Bolivian desert, where Greene is indeed finalising the coup. As the various parties depart, Bond infiltrates the hotel, killing the departing Colonel of Police for killing Mathis and sets off a chain of explosions when a hydrogen fuel tank is destroyed. Camille shoots Medrano and Bond captures Greene. After interrogating him, he uncharacteristically leaves Greene stranded in the middle of the desert with only a can of oil. Bond and Camille drive to a train station, where they finally kiss before she departs.
Bond goes to Kazan, Russia, where he confronts Vesper Lynd's former boyfriend, Yusef. Yusef is a Quantum henchman who specialises in seducing high-ranking women to get them to give up government assets as he stages his kidnappings, and is doing the same with Canadian agent Corinne Veneau. Bond has Corrine alert the Canadian Security Intelligence Service as he confronts Yusef. Later, Bond leaves Yusef's apartment and is confronted by M who is surprised that Bond did not kill Yusef. M reveals that Leiter has been promoted at the CIA, and Greene was found in the desert shot dead with oil in his stomach. Bond sets out into the cold night, aware that Mr. White and Quantum are still on the loose. In the final shot we see Bond throwing Vesper's Algerian loveknot necklace into the snow signifying his acceptance of the past and also the beginings of a more cool and collected Bond.
