In Moscow, Viktor Chagarin (Sergei Kolesnikov), a high-ranking, but corrupt Russian official, plans on incriminating political prisoner, former billionaire and government whistleblower, Yuri Komarov (Sebastian Koch), without a fair trial when Komarov refuses to hand over a secret file believed to have convicting evidence against Chagarin. In a separate incident, Jack McClane (Jai Courtney) is arrested as a result of an assassination attempt but agrees to testify against Komarov for a shorter sentence. John McClane (Bruce Willis), who has not been in touch with his son for several years, learns of his son's actions and travels to Russia to help.
When John finally arrives and approaches the courthouse that holds Komarov on trial, an explosion suddenly orchestrated by Chagarin and his henchmen occurs in the courthouse, and Jack breaks free with Komarov. Seeing his son, John confronts him, but their dispute is cut short when Chagarin's henchmen, led by Alik (Radivoje Bukvić), chases them in a Ural Typhoon MRAP on the streets of Moscow. John and Komarov manage to escape.
Hiding in a safe house, John finds out that his son has been a CIA officer in an undercover operation for the past three years. Jack's partner, Collins (Cole Hauser), demands the file's location from Komarov so that the CIA can bring Chagarin down, but Collins is soon shot by Chagarin's men and dies, as John and Komarov survive subsequent heavy gunfire and escape again.
They make their way to a hotel in the city to find the key to a vault containing the file. There, they meet Komarov's daughter, Irina (Yuliya Snigir), whom they earlier planned on joining with, but John grows suspicious of her, which is proven correct when Alik and his men crash in and tie John and Jack up, while Komarov is taken as a hostage, and Irina confesses to snitching on them for the "millions of dollars" to be gained. Jack breaks free of his ties and kills the nearest guards using a Russian gun-knife allowing the two to kill most of the men. Alik and the rest of the henchmen come back on a helicopter and try to kill them, but the two manage to escape.
That night, the two steal a car full of firearms and drive to Pripyat, Ukraine, the location of the vault that houses the file. When they arrive, they find that Komarov, Irina, and Alik have already arrived, but what they don't know is that on their way there, it was revealed that there was never a file in existence, and that the drawer with the file inside was actually the secret passage to a vault containing a large amount of weapons-grade uranium. Komarov kills Alik and calls Chagarin to tell him that he and Irina had manipulated the entire sequence of events since the beginning in an attempt to obtain the uranium and get revenge on Chagarin. Chagarin is then killed by a subordinate of Komarov.
At this point, John and Jack enter the vault, discover Komarov's true plot, and capture him. Irina, with another henchman, comes to her father's aid, but before they can escape, Jack goes after Komarov, while John goes after Irina, who is escaping on a Mil Mi-26 helicopter. Irina tries to protect her father by firing the helicopter's cannons at Jack, but John is able to bring the helicopter out of balance by driving a truck in the hangar section, still shackled by a chain, out of the open rear ramp of the helicopter; he is later thrown off into the building. Komarov remarks that Jack will get to watch his father die, which enrages Jack to hurl him off the rooftop into the path of the spinning helicopter's rotors, killing him.
As Jack reunites with John inside the building, Irina, wanting to avenge her father, rams the helicopter into the building in a suicide attack, but both father and son survive by leaping off the building and into a large pool of water as the helicopter crashes and explodes, killing Irina. John and Jack go back to New York and reconcile with John's daughter - and Jack's sister - Lucy McClane (Mary Elizabeth Winstead) on the tarmac.