Two Americans were waiting to cross the border when an unidentified gunman approached the line of vehicles waiting at the San Ysidro border crossing and fired into the men's pickup truck, hitting the victims in the head, arms and body, prosecutors in Baja California state quoted witnesses as saying.
The state Attorney General's Office said the men were U.S. citizens aged 25 and 28.
A State Department official later confirmed the nationality of the the two victims: "We can confirm two U.S. citizens were shot to death at a Tijuana border crossing today. Consular officials are in contact with Mexican authorities. No further information is available at this time."
Investigators said they found 9-mm shell casings at the scene. That ammunition is used in weapons favored by drug cartel gunmen in Mexico.
The shooting occurred before dawn Monday. The men's pickup had California plates.
Both victims were dead by the time authorities arrived.
The Associated Press contributed to this report.