The facility was opened in 1983, and was constructed primarily to divert growing commercial truck traffic from the busy San Ysidro Port of Entry, located 5.2 miles (8.4 km) west.

Commercial importations through Otay Mesa accounts for billions of dollars' worth of freight.

[1] The Otay Mesa Port of Entry is accessed by California State Route 905 on the northern side.

Since commercial traffic cannot use the San Ysidro Port of Entry, for commercial traffic Otay Mesa is the southern terminus of the Interstate 5 corridor.

A similar facility will be located at the Laredo International Airport, where Mexican customs officers will pre-inspect air shipments into Mexico.