Masoli transferred from CCSF to the University of Oregon in 2008. In 2008 for the Ducks, Masoli emerged from the 3rd string quarterback to starter as injuries plagued the depth chart. He threw for 13 touchdowns and 5 interceptions, while also rushing for 10 touchdowns. His 714 rushing yards in 2008 set an Oregon record for quarterbacks. Masoli led the team to a 42-31 victory against Oklahoma State in the 2008 Holiday Bowl.
Masoli was named to the Davey O’Brien Award watch list for the 2009 college football season. Masoli was College Football Performance Awards National Performer of the Week (vs. Arizona) and one of four Ducks included on the College Football Performance Awards in their midseason trophy list. He also appeared on the cover of the August 2009 issue of Sports Illustrated, along with center Jordan Holmes.
Masoli helped the Ducks win the Pac-10 Championship, advancing them to the Rose Bowl where they lost to the Ohio State Buckeyes 26-17. Masoli was 9/20 passing with 81 yards and an interception, while rushing for 9 yards and a touchdown.
For the season, he completed 177 of 305 passes for 2,147 yards and 15 touchdowns, and ran for 13 scores. His 2,815 yards of total offense stands eighth on the school’s single-season list.
Masoli was suspended for the entire 2010 season after pleading guilty to a felony burglary charge. Prior to his being kicked off the team, he would have been eligible to play in the 2011 season had he satisfied the requirements set forth by Oregon head coach Chip Kelly. On June 9, Masoli was dismissed from the team after a citation for marijuana possession.On June 16, 2010, Masoli pleaded guilty to marijuana possession and a traffic citation
USA Today, The Commercial Appeal, and other media outlets reported on July 25, 2010 that Masoli had sent his scholarship release papers to a number of schools, notably Ole Miss. The report included Ole Miss rival Mississippi State, Hawaii, UNLV, Louisiana Tech, and Syracuse. Masoli would presumably be eligible to play in the 2010 season after completing his undergraduate degree at Oregon; he would need to enroll in graduate study not currently offered at Oregon in order to be eligible at the next institution