The film opens with a flashback sequence revealing the events of Fast Five from a new perspective. It shows Dante Reyes (Jason Momoa), the son of the deceased Brazilian drug lord Hernan Reyes, watching his father's demise during the massive vault heist in Rio de Janeiro. This scene establishes Dante's twelve-year fixation on revenge against Dominic Toretto (Vin Diesel) and his family.

In the present day, Dom and Letty Ortiz are enjoying a quiet, domestic life with their son, Little B, while the rest of the crew is scattered globally. Dom receives a highly classified mission from Mr. Nobody's agency (now led by his daughter, Tess), concerning a potential threat in Rome.

The crew heads to Rome for what they believe is a simple retrieval mission, but it is quickly revealed to be an elaborate trap orchestrated by Dante. Dante frames the crew for an attack on the Vatican City that uses a massive rolling bomb, causing widespread destruction. The global intelligence community, led by the ruthless new agency head Aimes, immediately brands Dom and his family as international terrorists.

The team is forced to split up and go on the run. Dom and Letty are separated; Letty is captured and sent to a black site prison, while Dom evades capture and attempts to clear their names. Dom travels to Brazil, seeking help from old allies and discovering Dante's true goal: to make Dom suffer by systematically dismantling everything he loves, rather than simply killing him.

Meanwhile, Dante continues his psychological war, targeting key members of the crew individually. He uses advanced technology and cunning tactical maneuvers to seize control of their assets and vehicles. This leads to several spectacular action sequences, including a highway chase in Rome with the rolling bomb, and a fierce street fight in London involving Han, Roman, Tej, and Ramsey.

Letty, in the black site prison, unexpectedly encounters Cipher, her former nemesis. Cipher, who also has a history with Dante and sees him as a mutual enemy, forms an uneasy alliance with Letty to break out. Their escape involves a grueling, hand-to-hand combat sequence against prison guards and ends with them being airlifted to safety by Gisele Yashar, who is revealed to be alive.

The climax converges in Portugal, where Dante lures Dom and his remaining allies. Dante reveals he has captured Little B and plans to use him as bait to force Dom into an impossible choice: save his son, or save his scattered friends. This leads to a final, desperate car chase on a massive dam.

Dom, with the help of Jakob Toretto (who makes a heroic, self-sacrificial move to clear the road), manages to save Little B. However, Dante has one last devastating move: he traps Dom and Little B at the base of the dam and detonates two massive fuel tankers, causing a devastating explosion and collapsing the dam's structure, seemingly leaving Dom and his son with no viable escape.

The film ends on a dramatic cliffhanger, with the fates of Dom, Little B, and the rest of the fragmented crew who are now targeted by Aimes, revealed to be secretly working for Dante all left uncertain.