In California, I-80 runs 206 miles, beginning at its western terminus at U.S. Route 101 on the east side of San Francisco, to the Nevada border in the Lake Tahoe region of the Sierra Nevada to the west of Reno, Nevada. It passes through Berkeley, Vallejo, Vacaville and state capital Sacramento along the way. It is the highway that runs along the San Francisco-Oakland Bay Bridge, and just misses the latter city. I-80 has 7 of 9 possible spur routes within the Golden State, all within the Bay Area, with only I-180 and I-480 not existing in the state.

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I-80 in California additionally has a business route running through downtown Sacramento, and had a business route in Truckee in the Sierra Nevada until the mid-2000s.