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.

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.

Instead, I-280's northernmost extension, which includes a significant double-deck section (with northbound traffic on the lower deck and southbound traffic on the upper), primarily functions now as a spur into the Financial District, San Francisco, as suggested by signage on northbound US 101 at the Alemany Maze.

[15][16][17] A 26-foot (7.9 m) high faux-sandstone statue of Father Serra kneeling and pointing over the freeway is located at a highway rest area just north of the SR 92 intersection between the Bunker Hill Drive and Black Mountain Road exits on northbound I-280 in Hillsborough and can be clearly seen by drivers in both directions.

This also caused the completed freeway segment from the Bay Bridge approach/I-80 near 1st Street to The Embarcadero to be signed as part of SR 480 instead of I-280.

[3][18] After the 1989 Loma Prieta earthquake, plans to connect I-280 to I-80 were formally abandoned, the earthquake-damaged Embarcadero Freeway was torn down in 1991, and the northern terminus of I-280 was reconfigured to the present-day King Street on/offramps in 1997.

The three flyovers, with no connecting ramps, stood as a 110-foot-tall (34 m) monument to inefficiency for years in the 1970s, becoming the butt of local jokes.

The highlight prank occurred in January 1976, when a 1960 Chevrolet Impala was placed on the highest bridge overnight, where it obviously would be impossible to drive.

The following day, San Jose City Councilmember Joe Colla was photographed standing next to the car, an image that was circulated across many newspapers.

In 2010, a resolution was introduced in the state legislature to name it the Joe Colla Interchange in memory of the late councilmember.

[21] In 2021, University of California, Davis, researchers published a report on wildlife-vehicle collisions based on California Highway Patrol and insurance data over the past five years, according to which five of the 20 one-mile (1.6 km) stretches of highway in the state with the highest costs for this reason are on I-280, the worst being between San Bruno and Cupertino.