Interstate 280 (I-280) is a 57.22-mile-long (92.09 km) major north–south auxiliary Interstate Highway in the San Francisco Bay Area of Northern California. It runs from I-680 and US Route 101 (US 101) in San Jose to King and 5th streets in San Francisco, running just to the west of the larger cities of San Francisco Peninsula for most of its route.

From I-880 in San Jose to State Route 1 (SR 1) in Daly City, I-280 was built and dedicated as the Junipero Serra Freeway, after the Spanish Franciscan friar who founded the first nine of 21 Spanish missions in California from San Diego to San Francisco. One of the dedication signs (in Daly City) still indicates that the Junipero Serra Freeway is known as the "World's Most Beautiful Freeway" due to its scenic route through the San Francisco Peninsula. From SR 1 to the James Lick Freeway (US 101) in San Francisco it is officially called the John F. Foran Freeway (after a former member of the California State Legislature). From the James Lick Freeway to its northern end at King and 5th streets, I-280 is called the Southern-Embarcadero Freeway.

I-280 is one of two auxiliary Interstate designations to appear on opposite coasts of the United States. I-110 in California and Florida is the only other designation.

I-280 was formerly shown on the app icon for Apple's iOS and macOS built-in Apple Maps. This is because the highway goes through Cupertino, the home of Apple's headquarters.

The entirety of I-280 is defined in section 580 of the California Streets and Highways Code as Route 280, and that the highway is from "Route 101 in San Jose to Route 80 in San Francisco via Daly City". Route 280 was never fully constructed to I-80, its parent Interstate, as defined. The constructed northernmost segment of I-280 from 6th to 5th streets in San Francisco is also not considered an Interstate Highway according to the Federal Highway Administration (FHWA)'s route logs, but is still signed as such by Caltrans.

The southern end of I-280 is at the Joe Colla Interchange with US 101 in San Jose, where it acts as a continuation of I-680 westward. In between San Jose and San Francisco, I-280 passes through Santa Clara, Cupertino, Los Altos, and Los Altos Hills before it settles along its scenic route just to the west of the cities of the San Francisco Peninsula in San Mateo County and just to the east of the Santa Cruz Mountains. I-280 reemerges in a decidedly urbanized area in the city of San Bruno, passing through South San Francisco and Daly City before it runs across a southeastern swath of the city of San Francisco on the way to its northern terminus.

The segment of the Junipero Serra Freeway between Cupertino (SR 85) and Daly City (SR 1) has been called the "World's Most Beautiful Freeway" since its dedication in the 1960s. Drivers along this portion of I-280 are treated to scenic views of the Santa Cruz Mountains to the west and, at a few points, San Francisco Bay to the east and are isolated by hills from the cities to the east. Through much of this segment, the freeway is actually running just inside the eastern rim of the rift valley of the San Andreas Fault. A particularly attractive six-mile (9.7 km) stretch of the freeway from Hillsborough to Belmont provides a view at Crystal Springs Reservoir, formed by water piped over 160 miles (260 km) from Hetch Hetchy Valley in Yosemite National Park, partly filling the rift valley. The waters are impounded by Crystal Springs Dam, which drains into San Francisco Bay via San Mateo Creek; I-280 crosses the deep valley formed by this creek on the Doran Memorial Bridge, completed in 1969.

For nearly all of its length, I-280 runs roughly parallel and several miles to the west of US 101 (Bayshore Freeway). Both freeways are north–south routes connecting San Jose with San Francisco; however, unlike I-280, the route that US 101 takes between the two cities goes entirely through urbanized areas. The vast majority of the population of the San Francisco Peninsula lives somewhere between I-280 and US 101.