[4] From here, it begins its journey northward through San Jose, where it meets the Capitol Expressway, signed as County Route G21 (CR G21), about a mile (1.6 km) northeast of I-680's southern terminus.

[6][7] As it continues through Santa Clara County, it meets numerous local roads before interchanging with the Montague Expressway (CR G4).

Here, it exits San Jose and enters the city of Milpitas, where it meets SR 237, often referred to as Calaveras Boulevard.

[5] Amid Alameda County, it abruptly turns northeastward and enters a hilly area, where it crosses over Mission Pass, and descends into the Sunol Valley, where it runs concurrently with SR 84 for a short while.

Afterward, it enters Pleasanton and intersects with I-580, currently California's longest auxiliary Interstate providing access to Oakland and the Central Valley.

[4] In the wake of the September 11 attacks, a US flag was painted on a large piece of concrete on a hill along the Sunol Grade.

[19] As of January 2025[update], the HOT lanes' hours of operation is weekdays between 5:00 am and 8:00 pm; they are otherwise free and open to all vehicles at other times.

It was not yet paved south of Dublin, where it crossed Mission Pass between the Sunol Valley and the San Francisco Bay basin.

[27][28] At Martinez, the Martinez–Benicia Ferry took automobiles across the Carquinez Strait to Benicia, where Route 7, one of the original state highways from the 1910 bond issue, led north and northeast past Fairfield toward Sacramento and Oregon.

[33] The portion of SR 21 between Pleasant Hill and Martinez was finally added to the state highway system in 1949, as a branch of Route 75.

The same law, effective immediately as an urgency measure, authorized the Department of Public Works to acquire the ferry system, then operated by the city of Martinez, which was planning to shut it down.

[37] The Bureau of Public Roads approved urban routes of the Interstate Highway System on September 15, 1955, including a loop around the San Francisco Bay, soon numbered I-280 and I-680.

[41][42] A southerly extension, bypassing downtown Walnut Creek to South Main Street, opened on March 22, 1960, connecting with the SR 24 freeway to Oakland.

[48][49] However, until I-680 was completed in the early-to-mid 1970s,[44] it remained signed along the Nimitz Freeway, and the old road between San Jose and Warm Springs continued to be marked as SR 238.

[45] One more change was made to the routing of I-680: in July 1973, the remainder of SR 21, from Benicia to Fairfield, was added to the Interstate Highway System.