The drugs were found after agents spotted five trucks traveling north from the border with their headlights off, the El Paso (Texas) Times reported Monday.
Tire spikes were used to disable four of the trucks when they tried to flee. The fifth truck escaped back into Mexico.
Four men from the disabled trucks ran into the desert, but were tracked down by agents and arrested.
Some 6,940 pounds of marijuana with an estimated value of $5.5 million was found in the trucks, officials said.
The Saturday bust in the vicinity of Lordsburg, N.M., was in the same area that more than six tons of marijuana was seized in January from a caravan traveling along the same road.
Lordsburg, a town of about 3,400 residents, is located in a remote area of the state about 160 miles west of El Paso.