Darron Thomas went 11-for-15 for 206 yards and three touchdowns. Thomas also rushed 10 times for 67 yards.
Lavasier Tuinei caught four balls for 90 yards to lead the Ducks in receiving. He had scoring passes of eight and 34 yards.
Oregon (2-1) racked up 681 yards of total offense, including 416 on the ground.
"I think our guys focused on the task at hand and these are situations that I think sometimes can be difficult and that's what the problem with some teams are is that they overlook opponents. I thought our guys had a great week of preparation, they understood what the deal was," Oregon head coach Chip Kelly said.
Trevor Wooden threw for 91 yards on 6-for-13 passing in a losing effort for the Bears (0-3). He also led the team in rushing with 67 yards on 16 carries.
"He's going to keep getting better and better each and every week. He made some very nice throws and some slipped out of his hands. But he's got a lot to look forward to," Missouri State head coach Terry Allen said.
The Ducks won their 18th straight home game, while the Bears fell to 0-3 for the first time since 1994.
Missouri State got on the board first with a three-yard touchdown run by Chris Douglas, but Oregon quickly answered with a 10-play, 56 yard drive capped off by a James one-yard touchdown plunge.
Tuinei caught an eight-yard TD pass with 3:18 left in the first quarter to make it 14-7.
The Bears outgained Oregon, 147-98, in the first quarter, but their momentum was quickly halted as they failed to convert a 4th-and-1 at the Oregon seven- yard line on their first possession of the second period.
The 90-yard touchdown run by James highlighted a 21-point second quarter for the Ducks. They took a 35-7 lead into the break.
James rushed for his third and final score of the game on a 50-yard run in the third to make it 42-7.
The Oregon backups put two more scores on the board, including a 22-yard strike to Eric Dungy -- a redshirt freshman and son of former NFL coach Tony Dungy -- to cap off the scoring.
The 90-yard score by James was the longest in the 45-year history of Autzen Stadium...James tied Derek Loville (1986-89) for the most career touchdowns in school history with 42...James rushed for 200 or more yards for the fourth time in his career...Saturday's game marked the first-ever meeting between the schools.