Port Director Oscar Preciado said it was the first time officials had shuttered the 24-lane border crossing to vehicular traffic since President Kennedy's assassination in 1963.
Three people in the vans suffered injuries and a person in a nearby car also was wounded in the unusually brazen smuggling attempt, U.S. authorities said. More than 70 people inside the vans were arrested.
Northbound traffic at the checkpoint, where about 40,000 cars cross daily from Mexico, was backed up into Tijuana for miles as San Diego police investigated. The secondary inspection area filled with potential witnesses from cars in the lanes near the shooting. By evening, the lanes approaching the crossing had been mostly cleared of traffic.
Smugglers on occasion attempt to run the border crossing, but rarely in such a coordinated fashion. The vans, one following the other, tried to speed by a booth where inspectors from Customs and Border Protection check identification and ask questions before determining a person's eligibility for entering the United States.
As the vehicles tried to run through, a Customs and Border Protection officer and an Immigration and Customs Enforcement agent fired multiple gunshots.
Officials also deployed a runner-alert system: An alarm blared and gates and metal barriers automatically blocked exits out of the secondary inspection area, which was already full of cars.
"They had to stop because of the traffic stopped in front of them," said Angelica De Cima, a spokeswoman for Customs and Border Protection.
There are numerous trafficking groups in Tijuana that specialize in smuggling illegal immigrants through the border crossing, but they typically try to hide them in trunks or hidden compartments. Attempts at smuggling so many across a port of entry at the same time are unusual.
The port, which was declared a crime scene by the San Diego Police Department, remained opened to pedestrians, but it was not clear when it would reopen for vehicles. Drivers were being encouraged to use the Otay Mesa Port of Entry a few miles east. Mexican authorities did not close the southbound lanes.
The three injured immigrants were taken to a hospital, where one was being treated for life-threatening injuries, said Maurice Luque, a spokesman for the San Diego Fire-Rescue Department. The fourth victim suffered injuries that were not life-threatening when one of the vans struck the victim's vehicle while trying to escape.
The shooting was the latest in a recent string of violent incidents along the California-Mexico border. Last week, U.S. Border Patrol agents in San Ysidro shot and wounded an alleged smuggler who was speeding toward them in a truck, and another agent was fatally shot in July by a suspected smuggler in a rural area of eastern San Diego County.