Teenage drug runner Cedric Beauville is captured and arrested by the Royal Canadian Mounted Police on the Canada-United States border in possession of large quantities of illegal Fentanyl pills.Everett University research scientist Dr. Tyrone Brower (Gary Oldman) is contracted by Northlight Pharmaceuticals to carry out a study in support of their newest product, Klaralon. The drug is being touted as the first non-addictive painkiller and is due to be released shortly as a replacement for Oxycodone. The study uncovers concerning results; Klaralon initially presents as non-addictive when taken daily for the first 7 days (parameters specified by Northlight), however after 7 days it becomes almost three times more addictive than Oxycodone. Realising the public health implications, Brower recommends to Northlight they delay Klaralon's release for further testing, which they object to. Board member Dr. Bill Simons (Luke Evans) tries to tempt Brower into changing his mind by offering a large research grant ($780,000), but Brower refuses. With Northlight being one of the university's main donors, Brower finds himself under pressure from department head Geoff Talbot (Greg Kinnear) to approve the study, but again is reluctant. Northlight begins leaking information to discredit his reputation, and Everett University revokes his tenure. Desperate, Brower becomes a whistle-blower and contacts the FDA, being put in contact with investigator Ben Walker (Scott Mescudi).Detroit based DEA agent Jake Kelly (Armie Hammer) has managed to infiltrate two large scale drug cartels running Fentanyl. One is run by the Armenian Mafia who operate pill mills across the US. The other is based in Montreal, Quebec controlled by drug kingpin Claude 'Mother' Veroche (Guy Nadon), who operates out of a nondescript restaurant called La Marina. Kelly intends to convince the two cartels to enter into business, so both leaders can be arrested at once when they meet. Kelly has personal motivation for bringing them down, due to his younger sister Emmie (Lily-Rose Depp) suffering from crippling heroin addiction. Kelly's relationship with Mother becomes strained when news of Cedric's capture comes to light, with Mother becoming concerned there is an informant in his organizations. Jake provides a report to his department. He says that the American mafia has recruiters who bring people from the homeless shelters to the clinics which are manned by doctors who prescribe Oxycodone. The recruiters are people who are paid $100 per recruit. The homeless ones have medicare cards and their prescriptions are covered by the govt. The doctors prescribe Oxycodone for any reason what-so-ever. Now the cartels are pushing Fentanyl, which 100 times more potent than heroine. They want to control Fentanyl distribution in the US. Due to operational funding concerns, Kelly's superior agent Garrett (Michelle Rodriguez) gives him a reduced timescale to organize the meet between the two cartels. Mother has Cedric killed in police custody for his silence (before he starts taking names), and executes his second in command Guy Broussard (Éric Bruneau) after discovering he has been speaking with the Canadian Mounty Police (Due to his information, the Canadian police was able to intercept the run by Cedric). Mother indicates to Kelly that the bust on the border was impossible without an insider, as it was not a patrolled stretch. Kelly offers to buy $3 MM worth of Fentanyl from Mother on behalf of the Armenians, to entice Mother to come for the meeting. He knows Mother needs distribution. He tells the Armenians that they can turn the $ 3 MM into $30 MM on the streets easy. He offers to put $ 1 MM from his end, which is later authorized by Garrett.Architect and recovering Oxycodone addict Claire Reimann (Evangeline Lilly) becomes concerned when her 16-year-old son David does not return home from hockey practice. He is later found dead as a result of a Oxycodone overdose, shocking Claire who is convinced he never took drugs. Although the Detroit Police Department treats it as an accidental death (there were 40 overdose deaths in Detroit alone that week), she hires a private investigator who determines David was forced to take the Fentanyl (His lungs were perfect pink, which means no inhalation) and was murdered (there was trauma to the back of his head). Through her son's social media she tracks down one of his friends, who confesses several teenagers from the hockey team (from both Detroit and Montreal) work for Mother as drug runners, although David had only done it once. Reimann crosses the Ambassador Bridge and travels to Montreal where she hires another private investigator, who provides her with information on Mother and an untraceable ghost gun. She threatens another drug runner, Derrick Millebran (Duke Nicholson), who believes that Mother is killing them to tie up loose ends after Cedric's arrest. Kelly becomes aware of Reimann's activities through investigation of Cedric's associates, and intercepts her outside La Marina. He does not arrest her, but instead unloads her gun and urges her to leave for her own good.The meeting between the two cartels goes ahead, covertly monitored by a joint DEA-RCMP task-force. However, an RCMP surveillance officer accidentally gives away his position, resulting in a shootout that kills Kelly's partner, Special Agent Stanley Foster (Nicholas Jarecki). Mother also escapes, believed to have fled to Algeria. Given the seizure of the drugs at the meet, both US and Canadian agencies decide to disband the continued search for Mother and the Armenians. Outraged, Kelly goes against orders and travels to La Marina, where he threatens an employee who tells him Mother is still in Canada but is planning to escape via seaplane that evening from the Port of Montreal. Reimann is also given this information from her private investigator. Kelly arrives at the port, but has been beaten there by Reimann, who opens fire and kills Mother as he makes his way to the aircraft. His bodyguard shoots her in the arm, but is swiftly shot by Kelly. He then replaces the men's weapons with Reimann's ghost gun and his own unregistered back up gun, to make it appear they shot each other in a disagreement over money that was being carried by Mother at the time. He treats her gunshot wound, and tells her he does not intend to arrest her.A last ditch effort by Northlight CEO Dr. Meg Holmes (Veronica Ferres) also fails to convince Brower to come on side, and the company is subjected to an FDA hearing. To Brower's shock, the agency does not revoke Northlight's permissions for Klaralon's release, noting that the potential benefits to the public outweigh the dangers highlighted by his study. Walker is also reassigned as a retaliatory measure. Despite the legal risk, Brower breaks his non-disclosure agreement and goes to the press, finally getting the information public. His integrity and honesty pays off, and he is later hired by the University of Michigan due to his actions, and is seen giving an introductory lecture to a crowded auditorium.