The game's plot revolves around both Casino Royale and Quantum of Solace, with added gunfights and action sequences for gameplay. Many of the game's events were altered for gameplay purposes, and some of the events do not coincide with those of the actual films.
The game begins with James Bond in Lake Como, Italy where Bond is sent to abduct Mr. White from his home. After fighting the resistance at the White estate, Bond successfully escapes with White. White is taken to Siena, Italy where Bond and M interrogate him for information regarding Quantum, an organization unknown to MI6 at the time. White escapes with the assistance of M's bodyguard, Mitchell, who is revealed to be a traitor. Bond chases Mitchell through the rooftops and engages him in combat, resulting in Mitchell's death.
The game then takes Bond to Lake Constance in Austria, where members of Quantum meet up to discuss the "Tierra Project." Amongst them is a key member, Dominic Greene, who poses as an environmentalist. Bond disrupts their meeting, takes photos of the Quantum members, and escapes the area. The plot fast forwards to Camille Montes and Bond crash landing in Greene's intended land acquisition in Bolivia. Bond endures a violent gun fight to reach Camille. He soon learns Camille is pursuing the man responsible for murdering her family: General Medrano. Learning this, Bond opens up to Camille, telling her that Quantum was responsible for the death of his former love, Vesper Lynd.
The gameplay then takes the form of flash backs from Casino Royale. Bond begins in Madagascar, having been recently promoted to Double 0 status. Bond pursues Mollaka, a bomb maker, through a construction site and embassy before killing him. Bond then travels to Miami Airport to stop a terrorist from destroying a Skyfleet airliner. He successfully stops the terrorist, and it is revealed the bomber was hired by Le Chiffre, a private banker to numerous terrorist organizations around the world. Le Chiffre had sold stocks of Skyfleet, using his clients' funds to bet against the market in order to receive profit after the airliner's destruction. Le Chiffre sets up a high stakes poker game at the Casino Royale in Montenegro in order to win back his client's funds.
Bond meets Vesper Lynd, an accountant from the Treasury, on his way to Montenegro. After their meeting, Bond fights off dealers from a drug organization spread throughout the train (a notable difference from the film). After combat, Bond arrives in Montenegro, where he comes face to face with Le Chiffre. After defeating Le Chiffre in the poker game, Vesper is kidnapped. Bond pursues the kidnappers but crashes his car and is taken hostage. He escapes and battles through Le Chiffre's barge to rescue Vesper. While he is successful, Bond and Vesper are re-captured by Le Chiffre's body guards. Near death, they are saved when Mr. White kills Le Chiffre for his recent actions, leaving Bond and Vesper alive.
Later on, Bond and Vesper begin a romantic relationship, and Bond resigns from MI6, acknowledging that his work could strip him of his humanity. Bond and Vesper travel through exotic locations, arriving in Venice. Bond receives a call from M, who informs him that the funds won from the poker game were never returned to the Treasury. He pursues Vesper, who is meeting members of Quantum. Bond fights off the Quantum members in a building collapsing into the Venice waters. Vesper allows herself to drown, feeling guilt over her betrayal.
The game returns to the storyline of Quantum of Solace, with Camille and Bond arriving at a hotel in the middle of the Bolivian desert, where Greene and General Medrano are meeting. Greene plans to fund Medrano's war against the Bolivian government in exchange for his desired land acquisition. (In the film, we learn Greene wants the land for the massive underground water supply, which is cut off from the rest of the country. With the land, Greene can become the major utility supplier in Bolivia and receive all profits). Bond battles Quantum members and kills Greene by igniting the hotel's fuel cells, causing the hotel to catch on fire. Camille eliminates Medrano and escapes with Bond just as the hotel explodes. Bond and Camille are then seen walking towards an MI6 helicopter, leaving the destroyed area.
The game ends with a scene not seen in the film. Mr. White and Guy Haines (another Quantum associate) review all of these events. Bond, who is seen outside spying on both of them, speaks with M about his findings. The final scene shows Bond going through the rain, ready to engage the Quantum members as the screen fades to black.