Early in the second quarter Washington narrowed Oregon's lead to 21-7, and Huskies coach Steve Sarkisian had hope.
But the No. 2 Ducks answered with two touchdowns and headed into halftime with a 35-7 advantage, leaving Sarkisian and the rest of the 23rd-ranked Huskies deflated.
Saturday night's game ended with a 52-21 Oregon victory.
"We really tried not to panic. We tried to stick to the plan," Sarkisian said. "We got a good drive in there to get it to 21-7 and then it got sideways on us fast."
Marcus Mariota threw for 198 yards and four touchdowns and Oregon (6-0, 3-0 Pac-12) won its ninth straight overall dating back to last season, as well as its ninth straight in the series against the rival Huskies (3-2, 1-1).
Mariota hit Colt Lyerla with touchdown passes of 10 and 13 yards. Kenjon Barner, who went into the game ranked 10th in the nation with an average of 121 yards rushing per game, ran for 122 yards.
Bishop Sankey ran for 104 yards and two touchdowns for Washington, while Keith Price threw for 145 yards and two interceptions.
"Really frustrating. We were moving the ball at times in the first half but we couldn't finish," Sankey said. "We shot ourselves in the foot too many times."
The game was the latest in the lengthy Pacific Northwest rivalry.
Huskies' fans remember "The Pick" in 1994 when freshman cornerback Kenny Wheaton saved the day for the Ducks when he intercepted a pass by Damon Huard and ran it back 97 yards for a score.
The victory sent Oregon to the Rose Bowl — and a clip is still played on the video scoreboard for fans before every home game.
The Huskies raised the ire of Ducks' fans in 2002 when, after beating Oregon 42-10, the team danced for nearly an hour on the "O'' on the 50-yard line at Autzen Stadium.
But because of Oregon's recent domination of the series, the intensity of the rivalry has diminished in recent years. The Ducks' nine-game winning streak is the longest for either side in the series history, which dates back to 1900.
There was little visible contentiousness between the two teams on Saturday night, except for a brief shoving match in the third quarter. Some of the players said there was a bit of trash talking.
De'Anthony Thomas opened the scoring for the Ducks when he wove his way through several defenders for a 16-yard touchdown, set up when the Huskies fumbled on a punt return and Oregon's B.J. Kelley recovered on the Washington 20.
Mariota found sophomore Keanon Lowe with a 21-yard scoring pass before Avery Patterson scored on a 43-yard interception return. It was Patterson's second straight game with an interception return for a touchdown.
Sankey, who had also run for 100 yards in each of Washington's previous two games, had a 1-yard touchdown dive for the Huskies to make it 21-7 early in the second quarter.
The Ducks answered with Mariota's 10-yard TD pass to Lyerla. A short time later, a running Mariota hit Josh Huff with a 34-yard catch-and-run.
Rob Beard, who missed a 41-yard field goal attempt in the first half, made a 28-yarder early in the second to make it 38-7.
Sankey ran for a hard-fought 6-yard touchdown before the end of the third quarter.
Lyerla opened the fourth with a 13-yard touchdown pass from Mariota, and a short time later Byron Marshall ran for a score to make it 52-14.
Erich Wilson had a 1-yard TD run for Washington with 32 seconds left in the game.
"I don't think the final score is indicative of their football team as compared to ours and that part's really frustrating to me," Sarkisian said.
Washington popped into the rankings last week after a 17-13 victory over then-No. 8 Stanford.
The Ducks were the Huskies' third top-10 opponent this season. Washington also fell 41-3 to then-No. 3 LSU.
They struggled as much against the Ducks, who went into the game averaging more than 52 points a game and 550 yards in total offense.
Last season, Oregon defeated Washington 34-17 in the final game played at the old Husky Stadium before an extensive renovation that is set to be completed for the 2013 season.