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A zombie outbreak erupts in metropolitan areas around the world; those bitten by the creatures become zombies themselves within several (twelve) seconds. Retired United Nations (UN) investigator Gerry Lane (Brad Pitt), his wife Karen (Mireille Enos), and their two daughters manage to escape the outbreak in Philadelphia and take shelter with a family in Newark while waiting for special evacuation the next day, thanks to Gerry's friend UN Deputy Secretary-General Thierry Umuntoni (Fana Mokoena). They find a shelter for the night while waiting for a rescue helicopter. Their hosts choose not to accompany them when they flee the next day and are subsequently bitten and changed by zombies. Their son, Tommy, manages to escape, and Gerry's family takes him in. They are flown to an offshore U.S. Navy carrier group near New York where Umuntoni is overseeing the remaining worldwide governments' reactions.
The scientists there believe they must first find the cause of the zombie outbreak, believed to be in South Korea. A team of U.S. Navy SEALs is dispatched to go and defend Gerry. Gerry is coerced into going with them under the threat of having his family sent to a potentially unsafe mainland refugee camp. The team lands at Camp Humphreys in Pyeongtaek, Gyeonggi-do, where the surviving soldiers hold back zombie attacks. Gerry learns that a Korean doctor was the first to come down with the rabies-like infection, after being bitten by a soldier he was treating, whom local villagers had captured when he tried to attack them. A former CIA operative held at the base for selling arms to North Korea reveals that Israel had reacted a week before the outbreak, building giant walls around Jerusalem, and suggests that Gerry talk to Mossad agent Jurgen Warmbrunn.
Gerry is flown to Jerusalem and is brought to Warmbrunn (Ludi Boeken). The Mossad agent reveals they had intercepted a message from the Indian Army on fighting the rakshasa ("undead"). He and other Israeli experts convinced the government to build the wall to protect themselves, but allowing all uninfected people to move in. As Gerry is escorted back to his plane by the Israel Defense Forces (IDF), zombies are drawn to the loud music and singing in the city and pile themselves against the wall, forming a mound of bodies that allows many to clear the wall. As the city is quickly overtaken, Gerry and the IDF soldiers battle their way to escape. On their way, Gerry notices that the zombies avoid attacking an elderly man and, in another instance, a young feeble boy. A zombie bites Gerry's IDF escort; he quickly amputates her hand, which prevents her from being infected. Eventually, Gerry and the same female IDF escort, who identifies herself only as Segen, are able to board the last passenger jet leaving the city.
Gerry recounts the zombie attacks and remembers seeing sick, injured, and elderly people passed over by the zombie hordes, which leads him to believe this is evidence of some way to deal with them. He contacts Umuntoni to help convince the pilots to take them to Cardiff where an operational WHO (World Health Organization) facility is located. Nearing approach, a single zombie is discovered on the plane, and most of the passengers are quickly infected and converted. Seeing no other option, Gerry uses a grenade from Segen's pack to rupture the cabin and blow out the zombies, but in the process, causes the plane to crash. Gerry and Segen survive, though Gerry is impaled by debris from the crash. They make their way to the WHO facility where Gerry blacks out and falls into a coma.
Gerry wakes up a few days later nursed back to health. He contacts Umuntoni to help convince the WHO employees of his identity, but learns that Karen and his family were shipped to the mainland as they presumed he had died in the plane crash. Gerry explains his theory that the zombies ignore the infirm for the healthy, and suggests injecting themselves with a deadly but curable disease to mask themselves from the zombies. The WHO scientists agree but point out the pathogens are located in one of the zombie-infested labs. Gerry, Segen, and an Italian WHO scientist carefully work through the infested labs but are detected. Segen and the scientist get to safety, while Gerry finds himself in the vault with the pathogens and becomes cornered by a lone zombie. Without the knowledge to identify the strains in storage, many of which could kill him, Gerry injects himself with one of the samples and finds himself still alive. His hypothesis is proven correct as the zombie enters the vault but does not attack, allowing him to walk back to safety with more samples as the rest of the zombies run right past him. Gerry is then treated for the disease.
Later, as Gerry and Segen are taken to the mainland refugee camp in Nova Scotia where Gerry is reunited with his family, he explains they were able to use these diseases to create a masking agent, allowing them to rescue refugees still trapped by zombies and fight against them. He says that this isn't the end and the war has just begun (Paris and Venice are seen burning and overrun, with Russians fighting face to face with zombies for control of Moscow), but there is hope as people have used the masking agent to evacuate people or fight back.