Emily (Liberato) and her boyfriend, recent college dropout Randall (Le Gros), decide to spend some quality time together at his parents' vacation home. Once there, they are met by Jane (Nagel) and Mitch (Weber), old friends of Randall's father, who have arrived at the property for down time of their own. Agreeing to share the sprawling beach house with each other, the couples end the night partaking in some recreational drugs Randall brought with him. Shortly thereafter, a strange fog rushes into the house, which they chalk up to the drugs, and the group passes out immediately. As Emily wakes up, she knows that something is terribly wrong. With the fog still settling in, Jane covered in lesions, Randall severely sick and all the running water they can access now a disgustingly thick texture, it becomes clear that they — and the world around them — have been exposed to a life-ending illness.
After being caught in an undercover operation, a CIA agent referred to only as "Protagonist" (Washington), takes a cyanide pill in order to protect his team's secrets. Protagonist later awakens in the hospital only to be told that the mission failed, and the situation that led to his taking the pill was nothing but a test of his loyalty. Having passed said test, he has been cleared for employment by an ultra-secret organization known as Tenet, where he is introduced to a scientist, Barbara (Poésy), and his handler, Neil (Pattinson), who brief him on Tenet's focused time-based and time-altering missions. Protagonist's assignment: Sator (Branagh), a Russian oligarch who intends to destroy all past and future timelines.
After her husband, Doug (Caviezel), is put on trial by the Iranian regime for speeches centered in his beliefs, Elizabeth (Karvan) attempts to coax the American State Department into saving him and bringing him back home. Once it's made clear that his well-being is of no interest to the government, Elizabeth decides to visit the Middle East to save her spouse herself.