In Guerrero, Mexico, Don Miguel braces for competition as he struggles to keep control of the local poppy fields and protect his area. Back in Columbus, Ohio, Detective Mark Edwards orchestrates a traffic stop to close in on a local heroin dealer and starts to work his way up the chain. In Atlanta, Skyler moves back home with his parents to get clean, but a relapse threatens to tear his family apart.

Don Miguel responds to a shooting in his territory as drug-related violence in Mexico continues to escalate. In Columbus, Detective Mark Edwards investigates the overdose death of a young mother and tries to charge the person who gave her the deadly heroin. Nearby in Dayton, Richard runs a recovery clinic while struggling to help his daughter Brittany deal with her own heroin addiction.

In the border town of Juarez, a trafficker explains how heroin is transported to the US as Mexican Federal police undertake an operation to bust a dealer. In Columbus, Special Agent James executes a significant drug bust and starts tracking the local heroin supply back to its cartel sources when a key suspect disappears. In Atlanta, John hits the street to feed his habit before an impending court date but feels guilty for manipulating his family.

In Columbus, Sergeant Nate Smith helps recovering addicts get treatment while zeroing in on a dealer who's mixing heroin with lethal Fentanyl. In Mexico, Don Miguel finds himself trapped in the drug trade, while Mario, a young activist, looks for his missing brother. Back in Atlanta, Skyler signs himself up for long-term treatment but struggles to follow through. Series finale.

Don Miguel celebrates a birthday as his rivals close in, while Mexican Federal police move to crack down on drug trafficking in Guerrero. In Columbus, Special Agent James tracks down the missing suspect that may be the key to breaking open his case. Meanwhile in Akron, Laura and Dan locate their fugitive son Andrew and convince him to turn himself in for outstanding drug charges and enter rehab.