Kani Benoit ran for 138 yards and two touchdowns, including a career-long 68-yard scoring dash for Oregon (4-1, 1-1 Pac-12) in the fourth quarter.
But the victory was costly for the Ducks, who lost Herbert along with running back Royce Freeman and starting receiver Dillon Mitchell to injury in the first half. Backup QB Taylor Alie left the game in the fourth quarter. And starting safety Tyree Robinson was ejected for targeting.
Ross Bowers threw for 255 yards and three touchdowns for the Golden Bears (3-2, 0-2). Kanawai Noa caught seven passes for 126 yards and a score. Cal finished with just eight net rushing yards for the game.
Aiden Schneider kicked a 42-yard field goal to cap Oregon's first series of the game. The Ducks added to the lead on Herbert's 37-yard scoring pass to Brenden Schooler, but then the injuries started piling up.
Freeman headed for the locker room with what appeared to be a shoulder injury. Oregon's top rusher with 541 yards and 10 TDs going into the game, Freeman had rushed for 51 yards before he was hurt.
Herbert ran for a 7-yard touchdown to make it 17-0 but then left the sidelines with an unspecified injury. He was replaced by Alie.
Robinson was ejected for targeting late in the first quarter.
Mitchell, who led the Ducks with 217 yards receiving and two scores going into the game, also left with an injury. The Ducks were already without senior Charles Nelson because of a right ankle sprain.
Late in the opening half Alie was intercepted by Jordan Kunaszyk and the Golden Bears capitalized on the next play with Bowers' 18-yard touchdown pass to Jordan Veasy to narrow the score to 17-7.
Benoit's 1-yard scoring run gave Oregon a 24-7 lead early in the third quarter. Cal answered with Bowers' 75-yard pass play to Kanawai Noa. Matt Anderson added a 36-yard field goal early in the fourth.
After Benoit's long touchdown, Alie was injured and was replaced by Braxton Burmeister, who made his first college appearance. The Ducks nonetheless padded the lead to 38-17 with Tony Brooks-James' 5-yard touchdown run.
Bowers found Vic Wharton III with a 28-yard scoring pass for Cal, but Oregon true freshman Darrian Felix scored on an 11-yard run for the final margin.
Cal was coming off a 30-20 loss at home to USC. The road trip to Eugene was the Golden Bears' first since their season-opening victory at North Carolina.
The Ducks were coming off a 37-35 loss to Arizona State last week in Tempe. It was Willie Taggart's first loss as Oregon's coach.
California: Coach Justin Wilcox is a native of nearby Junction City, Oregon, and played for the Ducks at defensive back. His family is close to Herbert's family.
Oregon: Herbert tied an Oregon record with six touchdown passes in a loss to Cal in Berkeley last season. ... Tight end Jacob Breeland did not dress for the game.
Cal plays at No. 6 Washington, which beat Oregon State 42-7 earlier Saturday in Corvallis.
Oregon hosts No. 16 Washington State, coming off a 30-27 victory over No. 5 USC on Friday night in Pullman.