In a flashback in snowy Norway, a young Madeleine Swann witnesses her mother being murdered by Lyutsifer Safin, who is seeking revenge against her father Mr. White. Madeleine manages to shoot Safin and thinks she has killed him. As she drags Safin out of her house he suddenly regains consciousness. She attempts to flee but falls through thin ice on a frozen lake. Trapped beneath the ice, she begins to drown looking up at Safin. Instead of killing her, Safin shoots a hole in the ice and pulls her out of the lake.
In the present day, sometime after Ernst Stavro Blofeld's capture, James Bond is on vacation with Madeleine in Matera, in Southern Italy. Madeleine urges Bond to forgive Vesper, and Bond agrees to visit Vesper's grave (the reason Madeleine brought them there) in exchange for Madeleine telling him her secrets. Vesper's grave is trapped, and Bond is nearly killed by a bomb. As Bond takes Madeleine to safety a team of Spectre agents lead by Primo appear and attempts to kill them both. Bond is able to use his tricked-out DB5 to kill nearly all of the assassins (Primo escapes), but he believes that Madeline must have betrayed him just as Vesper did. He gets Madeleine to a train station, puts her on a train, tells her he will never see her again and stays at the station while the train departs.
Five years later, Spectre agents led by Primo kidnap Dr. Valdo Obruchev from a secret MI6 laboratory. It turns out that he had been developing a secret weapon codenamed "Project Heracles", nanobots programmed using DNA samples to kill specific targets (and their blood relatives) within moments of infection, but it is harmless to anyone else. The nanobots can be passed from person to person like a disease, making it an almost untraceable and unstoppable weapon of assassination.
Bond, retired and living in Jamaica, is asked by his friend CIA agent Felix Leiter along with Leiter's colleague from the State Department Logan Ash to find Dr. Obruchev. At first Bond declines, but an MI6 agent named Nomi contacts him. She tells him she has succeeded him as 007 following his retirement and warns him not to pursue Obruchev. Bond decides to help Leiter after all.
Bond arrives in Cuba and meets with a CIA agent named Paloma, one of Leiter's allies. The two infiltrate a Spectre meeting which is celebrating Blofeld's birthday in order to find Obruchev. Obruchev is present at the party programming a set of the Heracles nanobots, but he switches the target profile that Primo gives him. At the party, Blofeld uses his bionic eye to communicate with the leaders of Spectre, inviting them to watch Bond's demise. Heracles is released from ceiling sprayers over the whole party. Bond remains unharmed and the nanobots kill all of the Spectre leadership present instead. Bond and Paloma capture Obruchev and fight their way out of the party, stealing Orbuchev back from Nomi. Bond tells Paloma that she performed excellently, and Bond steals Nomi's plane. He takes Obruchev to Leiter and Ash on a CIA fishing trawler of the coast, but as he tries to get answers from Obruchev Ash mortally wounds Leiter, revealing himself to be a double agent. He traps them both in the ship's hold and places a mine on the side before escaping with Obruchev. With the ship sinking, Leiter knows that he is dying and slowing Bond down too much. He tells his friend to let him go. Bond watches him die before escaping from the sinking ship.
Back in London, M asks Bond to reveal what he knows about the incident, but Bond insists on a meeting with Blofeld. M refuses to grant this. On his way out of M's office Moneypenny asks Bond to come with her to meet with Q. They fill Bond in on the weapon. After M discovers that his own staff are working with Bond behind his back he agrees to allow Bond to meet with Blofeld. Bond gives M Ash's name, and Nomi is assigned to find Ash.
M reveals that Madeleine is the only person allowed regular access to Blofeld in Belmarsh, as she is Blofeld's psychologist (at Blofeld's insistence). Posing as a patient, Safin visits Madeline. He reveals his identity and gives her a nanobot dose targeting Blofeld disguised as perfume. Bond meets with Madeleine at Blofeld's prison cell. Before Blofeld appears in the interrogation room Madeline realizes she doesn't want to kill Blofeld and orders them to let her out. Bond is unknowingly infected with the nanobots when he tries to get an explanation from Madeline before letting her leave. Alone together, Blofeld tells Bond that Madeline is the one who knows who has Heracles. Blofeld reveals to Bond that he had staged the ambush at Matera to make it look like Madeleine had betrayed him. Enraged, Bond chokes Blofeld for a few moments before he relents and backs off, but the nanobots kill Blofeld while Bond is explaining his actions to Tanner. Madeline has abandoned her car and disappeared.
Bond finds Madeleine at her childhood home in Norway where her mother was murdered. They reconcile, and Bond discovers that she has a five-year-old daughter named Mathilde. Madeline initially claims Mathilde isn't his daughter, despite Mathilde having Bond's blue eyes. Bond spends the night, and makes breakfast for Mathilde the next morning.
Madeleine shows Bond a secret room built by her father in the home, and reveals that when Safin was a boy, Blofeld ordered Mr. White to kill his entire family, thus earning Safin's ire against Spectre. Bond calls Q and gives him Safin's name. When he asks for an update Q shows Bond where Nomi is presently, and Bond realizes that Ash is en route to Madeline's home. Bond gets them out to a car and on the road just as Ash's men arrive. After a lengthy chase, Bond manages to kill Ash by crushing him under his own overturned car. However, Safin arrives by helicopter and kidnaps Madeleine and Mathilde.
M allows Bond and Nomi to infiltrate Safin's base in an abandoned island in disputed waters between Russia and Japan. The base is a WWII chemical plant and later missile silo that has been converted into a nanobot factory, where the weapon is being mass produced by Obruchev. Madeline and Mathilde are being held there by Safin, who shows them his poison garden. Primo is present, and reveals that he has shifted his allegiance to Safin.
As Bond and Nomi make their way into the base and kill several guards, Madeleine escapes custody from Primo. Nomi captures Obruchev and they plant explosives in the lab, but Safin uses the public address system to ask Bond to come meet him. Nomi notes that they didn't bring enough explosives to destroy the entire factory, but Bond decides to bluff and goes to meet Safin.
Safin is holding Mathilde hostage. He refuses to fully explain his plan to Bond, but it involves releasing Heracles on a mass scale, giving him the ability to kill nearly anyone in the world. Safin tells Bond that he will kill Mathilde unless he and Nomi disarm the bombs they have already planted and leave. Bond insults Safin, but then grovels and asks for forgiveness when Safin threatens Mathilde. The groveling serves as a distraction. Bond kills Safin's guards but Safin escapes with Mathilde through a trap door.
Under attack by Safin's guards, Obruchev says he could program Heracles to kill Nomi's entire race. She kills him by pushing him into the nanobot vat. Safin releases Mathilde after she bites his hand, and she hides. Bond finds Madeleine and Mathilde and gets Nomi to agree to take them off the island in a boat. Q detects several ships approaching the island, Safin's men ready to take and distribute Heracles. Despite political pressure from both Japan and Russia's government, M agrees to launch a missile strike from the nearby HMS Dragon that will destroy the factory. Bond stays on the island to open the silo doors so that the missile strike can penetrate the factory and destroy Heracles.
Bond fights his way up a staircase to the control tower that controls the silo doors, through waves of Safin's men. He is able to kill them all, including Primo, who he kills when he accidentally activates his EMP watch, which explodes Primo's bionic eye in his eye socket. Bond opens the silos and the missile strike is launched, but on his way out he sees the doors close again. With nine minutes until the missiles arrive Bond makes his way back up to the control tower, but Safin ambushes him in his poison garden. Safin shoots Bond several times and manages to infect both of them with a vial containing nanobots programmed to kill Madeleine and Mathilde. Despite his injuries, Bond manages to kill Safin. Bond confirms with Q by radio that the nanobots cannot be removed. Q says, "but they're harmless to someone who isn't the target" and Bond replies, "that isn't going to work for me." He re-opens the silo doors and climbs to the roof of the tower, asking Nomi to put Madeline on the radio. Bond tells Madeline that Mathilde is the most beautiful thing he has ever seen. Madeline complains that they need more time, and Bond says, "you have all the time in the world." Madeleine confirms that Mathilde has her father's eyes, and Bond's last words to her are, "I know. I know". From the rooftop Bond watches the missiles fly in and destroy the factory, killing him in the process.
In the aftermath, M, Q, Moneypenny, Tanner, and Nomi have a drink in Bond's honor at the MI-6 headquarters, leaving a symbolic filled glass for him, before deciding to get back to work. Madeleine drives off to Matera with Mathilde, telling her a story about a man named, "Bond, James Bond".
