A total of 76 suspects have been arrested and huge quantities of drugs and arms seized in a series of raids.
The ring used backpackers and vehicles to smuggle marijuana, cocaine and heroin across Arizona's western desert.
The network was linked to Mexico's Sinaloa cartel and generated an estimated $2 billion in profit over the last five years, officials said.
"Today we have dealt a significant blow to a Mexican criminal enterprise that has been responsible for poisoning our communities," said Arizona Attorney General Tom Horne.
"I find it completely unacceptable that Arizona neighbourhoods are treated as a trading floor for narcotics", he added.
The bust - known as "Operation Pipeline Express" - followed a 17-month investigation by multiple US law enforcement agencies.
A mix of US and Mexican nationals were arrested in three sweeps last week, earlier this month and in September, officials announced.
More than 30 tons of marijuana, 90kg (200lbs) of cocaine and 72kg (160lbs) of heroin were seized, as well as more than 100 firearms.
Operating from the Arizona towns of Chandler, Stanfield and Maricopa, the network ferried drugs across the Mexican border on foot and by vehicle to safe houses in the Phoenix area, officials said.
The drugs were then sold to criminal gangs who distributed them in other states across the US.
Officials believe the network made huge profits by securing a monopoly on smuggling routes along an 80 mile (128km) stretch of the remote desert border from Yuma to to the community of Sells in the Tohono O'odham Indian reservation.
Intelligence suggested the ring was linked to the Sinaloa cartel, led by Mexico's most-wanted fugitive drugs lord, Joaquin "El Chapo" Guzman.
"We in Arizona continue to stand and fight the Mexican drug cartels, who think they own the place," Pinal County Sheriff Paul Babeu said.
"This is America and we shall bring a crushing hand of enforcement against those who threaten our families and our national security".
US authorities say they have broken up a massive drug-smuggling network run by a Mexican cartel in Arizona.