More than 250 pounds of the synthetic opioid, which is 80 to 100 times stronger than morphine, was found inside a truck carrying Mexican produce.
The drug was found hidden Saturday morning inside a tractor-trailer after a scan during secondary inspection indicated something else was in the load, Nogales CBP Port Director Michael Humphries said.
Ingesting as little as 2 milligrams of fentanyl, equivalent to a few grains of table salt, can be lethal, according to the DEA.
Agents also seized a much smaller number of fentanyl pills and a large cache of methamphetamine and arrested the Mexican man driving the truck.
Mexican traffickers have been increasingly smuggling the drug into the United States, mostly hidden in passenger vehicles and tractor-trailers trying to head through ports of entry in the Nogales, Arizona, and San Diego areas.
Fentanyl has caused a surge in fatal overdoses around the U.S., including the 2016 accidental death of pop music legend Prince, who consumed the opioid in counterfeit pills that looked like the narcotic analgesic Vicodin.
U.S. law enforcement officials say the illicit version of the painkiller is now seen mostly as a white powder that can be mixed with heroin for an extra kick as well as blue pills that are counterfeits of prescription drugs like oxycodone.
U.S. Drug Enforcement Administration officials have said that while 85 percent of the illicit fentanyl is seized at San Diego-area border crossings, an increasing amount is being detected on the Mexican border with Arizona, a state where the Sinaloa cartel controls the drug trade and fatal fentanyl overdoses are rising.
The Centers for Disease Control and Prevention says in a recent report that fentanyl is now the drug most often involved in fatal overdoses across the country, accounting for more than 18,000, or almost 29 percent, of the 63,000 overdose fatalities in 2016.