In Marseille, an undercover police detective follows Alain Charnier, who runs the world's largest heroin-smuggling syndicate. The policeman is assassinated by Charnier's hitman, Pierre Nicoli. Charnier plans to smuggle $32 million of heroin into the United States by hiding it in the car of his unsuspecting friend, television personality Henri Devereaux, who is traveling to New York by ship.
In New York City, detectives Jimmy "Popeye" Doyle and Buddy "Cloudy" Russo go out for drinks at the Copacabana. Popeye notices Salvatore "Sal" Boca and his young wife, Angie, entertaining mobsters involved in narcotics. They tail the couple and establish a link between the Bocas and lawyer Joel Weinstock, who is part of the narcotics underworld.
Popeye learns from an informant that a massive shipment of heroin will arrive in the next two weeks. The detectives convince their supervisor to wiretap the Bocas' phones. Popeye and Cloudy are joined by federal agents Mulderig and Klein.
Devereaux's vehicle arrives in New York City. Boca is impatient to make the purchasereflecting Charnier's desire to return to France as soon as possiblewhile Weinstock, with more experience in smuggling, urges patience, knowing Boca's phone is tapped and that they are being investigated.
Charnier realizes he is being observed. He "makes" Popeye and escapes on a departing subway shuttle. To avoid being tailed, he has Boca meet him in Washington D.C., where Boca asks for a delay to avoid the police. Charnier, however, wants to conclude the deal quickly. On the flight back to New York, Nicoli offers to kill Popeye, but Charnier objects, knowing that Popeye would be replaced by another policeman. Nicoli insists, however, saying they will be back in France before a replacement is assigned.
Soon after, Nicoli attempts to shoot Popeye but misses. Popeye chases Nicoli, who boards an elevated train. Popeye commandeers a car and gives chase. Realizing he is being pursued, Nicoli works his way forward through the carriages, shoots a policeman who tries to intervene and hijacks the motorman at gunpoint, forcing him to drive straight through the next station, also shooting the train conductor. The motorman passes out and they are just about to slam into a stationary train when an emergency trackside brake engages, hurling the assassin against a glass window. Popeye arrives to see the killer descending from the platform. When the killer sees Popeye, he turns to run but is shot dead by Popeye.
After a lengthy stakeout, Popeye impounds Devereaux's Lincoln. He and his team take it apart searching for the drugs, but come up empty-handed. Cloudy notes that the vehicle's shipping weight is 120 pounds over its listed manufacturer's weight. They remove the rocker panels and discover the heroin concealed therein. The police restore the car to its original condition and return it to Devereaux, who delivers the Lincoln to Charnier.
Charnier drives to an old factory on Wards Island to meet Weinstock and deliver the drugs. After Charnier has the rocker panels removed, Weinstock's chemist tests one of the bags and confirms its quality. Charnier removes the drugs and hides the money, concealing it beneath the rocker panels of another car purchased at an auction of junk cars, which he will take back to France. Charnier and Sal drive off in the Lincoln, but hit a roadblock with a large contingent of police led by Popeye. The police chase the Lincoln back to the factory, where Boca is killed during a shootout while most of the other criminals surrender.
Charnier escapes into the warehouse with Popeye and Cloudy in pursuit. Popeye sees a shadowy figure in the distance and opens fire a split-second after shouting a warning, killing Mulderig. Undaunted, Popeye tells Cloudy that he will get Charnier. After reloading his gun, Popeye runs into another room and a single gunshot is heard.
Title cards note that Weinstock was indicted but his case dismissed for "lack of proper evidence"; Angie Boca received a suspended sentence for an unspecified misdemeanor; Lou Boca received a reduced sentence; Devereaux served four years in a federal penitentiary for conspiracy; and Charnier was never caught. Popeye and Cloudy were transferred out of the narcotics division and reassigned.