On a date called "the 14th", the Protagonist leads a covert CIA extraction during a staged terrorist siege at a Kyiv Opera House. He is saved from KORD by an oddly behaving operative with a red trinket. The Protagonist retrieves the artifact but his team is sabotaged, captured, and tortured. He swallows a suicide pill but wakes up to find it was a fake; a test that only he has passed. Recruited by a secretive organization known as "Tenet", they brief him on bullets with "inverted" entropy that move backwards through time. With his handler Neil, he traces them to Priya Singh, an arms dealer in Mumbai.

Priya reveals she is in Tenet and that her bullets were inverted by Russian oligarch Andrei Sator, who is communicating with the future. Sir Michael Crosby advises they approach Sator's estranged wife Kat Barton, an art appraiser who authenticated a forged Goya painting that Sator purchased from her friend Arepo, which he now uses to blackmail her. To get Kat's help, they try to steal the Goya from Sator's freeport facility at Oslo Airport, but are thwarted by two masked men who emerge from either side of a machine. In Mumbai, Priya explains it was a "turnstile", a device that inverts entropy – the two men were the same person, traveling in opposite directions through time; she reveals that Sator sabotaged his Kyiv CIA team but KORD got the artifact, plutonium-241, and are moving it through Tallinn.

Unaware of his Goya failure, Kat introduces the Protagonist to Sator, who plans to kill him until he mentions Kyiv. When he saves Sator's life after Kat tries to drown him, they cooperate to intercept the artifact. The Protagonist and Neil steal it in Tallinn but are ambushed by an inverted Sator holding Kat hostage. The Protagonist hides the artifact and rescues Kat, but they are recaptured and taken to Sator’s Tallinn freeport, where the inverted Sator interrogates them for the location of the artifact, shooting Kat with an inverted bullet. Tenet troops led by commander Ives arrive, but Sator escapes via a turnstile. To heal Kat's wound, they all invert. The inverted Protagonist drives back to the ambush to retrieve the artifact but encounters Sator who takes it.

To un-invert, the Protagonist must travel back in time to the freeport in Oslo and fight his past self to enter its turnstile, followed by Neil and a healing Kat. In Oslo, Priya tells him Sator now has all nine pieces of the "Algorithm", a device that future antagonists need to invert the entropy of the world and destroy its past. She planned for Sator to get the artifact so as to reveal the other eight pieces in preparing his dead drop. Based on his earlier conversation with Crosby, the Protagonist realizes it is a nuclear hypocenter detonated on "the 14th" in Sator’s hometown of Stalsk-12.

On a Tenet ship traveling back to "the 14th", Kat reveals Sator has terminal cancer and is omnicidal. They deduce he will return to a happy moment on a family vacation in Vietnam that was also on "the 14th" and commit suicide, sending the dead drop coordinates to the future via a dead man's switch. Arriving at "the 14th", Kat goes to Vietnam to pose as her past self and keep Sator alive until the Tenet forces in Stalsk-12 recover the Algorithm. They use a "temporal pincer movement", with both non-inverted and inverted troops making a diversionary attack so the Protagonist and Ives can discreetly steal the Algorithm before detonation. One of Sator's men, Volkov, traps them in the hypocenter, and Sa