San Ysidro is located in the southernmost part of San Diego County, immediately north of the international border with Mexico. It was annexed by the city of San Diego in 1957. Although the independent municipalities of National City, Chula Vista, Coronado, and Imperial Beach lie in between San Ysidro and the rest of San Diego, the two areas are connected by a narrow 400ft wide city boundary line that runs over the San Diego Bay. Thus, it is possible to travel across water from central San Diego to San Ysidro without leaving city limits.

San Ysidro is named for San Ysidro Labrador (Saint Isidore), patron saint of farmers. Furthermore, San Ysidro is the site of one the nation's first communes started by William Ellsworth Smythe, in 1908.

San Ysidro is home to the world's busiest land border crossing, where U.S. Interstate 5 crosses into Mexico at Tijuana. In the 2005 U.S. fiscal year, more than 17 million vehicles and 50 million people entered the United States at the San Ysidro port of entry. The great majority of these are workers (both of Mexican and U.S. nationality) commuting from Tijuana to jobs in the greater San Diego area and throughout southern California. There is also a thriving reverse traffic, both of workers traveling to maquiladoras in Mexico and those purchasing services (vehicle repairs, hair and beauty services, childcare, medical or dental) or seeking entertainment in Tijuana. Crossing times are often slow at San Ysidro, particularly for those entering the United States in cars. For this reason many cross on foot, the line for which is frequently much faster than the vehicle line. Some foot travelers own a car in each country, and keep them in one of the large parking lots located near the border post, or use the respective public transportation systems of both cities (both systems have a bus station built solely to serve the border crossing point, and the San Diego Trolley runs from downtown San Diego to the border crossing).