Masoli transferred from the City College of San Francisco 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. He also appeared on the cover of a regional August 2009 issue of Sports Illustrated along with center Jordan Holmes.
In October 2009, Masoli helped lead the #10 Ducks to an upset over the then #4 USC Trojans with 222 passing yards, 164 rushing yards and two touchdowns.
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.
On January 25, 2010, Masoli and teammate Garrett Embry were identified as suspects in a theft on the University of Oregon campus. On March 12, 2010, Masoli pleaded guilty to second-degree burglary, receiving 12 months probation. Masoli was then suspended for the entire 2010 season by head coach Chip Kelly.
In June, 2010, Masoli was cited for misdemeanor drug and traffic offenses, and was dismissed from the team. He later pleaded guilty to marijuana possession and a moving violation stemming from the traffic stop. 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 Kelly.
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.
On August 31, 2010, the NCAA denied Jeremiah Masoli's waiver for immediate eligibility at Ole Miss. In a press release, the NCAA stated that the transfer exception cited in Masoli's case is intended for students pursuing new academic study, not avoiding disciplinary punishments. Ole Miss appealed the decision, and school officials expected a response from the NCAA before Ole Miss's second game of 2010. Ole Miss coach Houston Nutt expressed his disagreement with the NCAA's ruling; some reports suggested that Masoli was likely to be named a team captain for 2010 given his eligibility. On September 3, 2010, the ad hoc NCAA Subcommittee for Legislative Relief granted Ole Miss's appeal, allowing Masoli to play immediately in the 2010 home opener versus Jacksonville State University.
For the season at Ole Miss, Masoli was 169-of-296 for 2,039 yards, 14 touchdowns, and thirteen interceptions. In addition, he rushed 121 times for 544 yards and six touchdowns, and he punted three times, averaging 43.7 yards per kick.
On April 9, 2011, at the Ole Miss Spring game, Jeremiah Masoli was honored with the 2010 Leadership Award from the Birmingham Alumni Club.
Masoli signed with the San Francisco 49ers as an undrafted free agent. He was waived by the team on August 22.
Masoli was drafted in the eighth round of the 2011 UFL Draft by the Omaha Nighthawks of the United Football League. On August 25, 2011, Masoli signed with the Nighthawks.
On April 10, 2012, Masoli signed with the Edmonton Eskimos of the Canadian Football League hoping to successfully convert from American football to Canadian football. He however spent his first season in Edmonton injured. On February 5, 2013 Masoli was traded to the Hamilton Tiger-Cats as part of a five-player trade. He played in both preseason games leading into the 2013 CFL season, completing 6 of 13 attempts for 88 yards with no touchdowns or interceptions.
In the 2013 regular season, he played in one game, completing one pass in two attempts for 12 yards and one touchdown. Masoli also rushed for 61 yards in 10 carries.
Masoli made his first CFL start in Week 4 of the 2014 CFL season, against the Calgary Stampeders, replacing the injured Zach Collaros. Masoli struggled and was replaced by Dan LeFevour in the third quarter.
Masoli began the 2015 CFL season as the third quarterback on the depth chart, trailing Zack Collaros and Jeff Mathews. Due to injuries Masoli was tasked with leading the Ti-Cats in their regular season game. In his lone regular season contest Masoli completed 11 of 21 attempts (52.4 completion percentage) for 148 yards with one touchdown and no interceptions. Masoli lead the Tiger-Cats over the Toronto Argonauts in the Eastern Semi-Final completing 12 of 18 passes for 141 yards with a touchdown and an interception. Jeremiah Masoli played an exceptional game on the road against the Ottawa Redblacks in the Eastern Final; completing 30 of 42 pass attempts for 349 yards with two touchdowns (the second with less than 2 minutes remaining in the game) and one interception. Nevertheless, the Tiger-Cats were defeated by the Redblacks, thus ending their 2015 season.
Masoli began the 2016 season as the second quarterback behind Zack Collaros, however due to Collaros's continued rehab from his 2015 knee injury head coach Kent Austin announced that Masoli would be the starting quarterback to begin the new season. Masoli lead the Tiger-Cats into the CFL's inaugural game at BMO Field and the 2016 season opener completing 27 of 37 pass attempts for 318 yards, with three touchdowns and no interceptions, en route to a 42-20 victory. On July 23, 2016, Masoli claimed the record for most consecutive completions in a single CFL game against the Edmonton Eskimos (coached by the previous record-holder, Jason Maas), completing 31 of 38 pass attempts, with 23 completions that were consecutive. This also became the largest comeback in the history of the Tiger-Cats, with the team scoring 31 points in the second half to win, 37-31. Starting quarterback Zack Collaros returned to the starting lineup for Week 8, relegating Masoli to the backup role, having gone 3-3 as the starter.2008 Holiday Bowl MVP
Pac-10 offensive player of the week for the week of November 21, 2009
AT&T ESPN All-America Player of the Week for November 21, 2009. As of August 6, 2011 San Francisco 49ers Head Coach, Jim Harbaugh announced during a press conference that Jeremiah Masoli would remain at the quarterback position, 3rd on the depth chart.
On the morning of January 24, 2010, a member of the Sigma Alpha Epsilon house returned home and witnessed Masoli and teammate Garrett Embry leaving an area of the house near his room. When he realized a projector and two laptop computers were missing he took chase. The victim chased down Embry, who returned the projector and subsequently reported the incident to Eugene police. Police interviewed Masoli the next day, where he said he was not at the fraternity house. On March 12, 2010, Masoli pleaded guilty to second-degree burglary before Lane County Circuit Judge Maurice Merten, who sentenced Masoli to one year probation and 140 hours of community service. As part of the plea agreement, this charge was later reduced to a misdemeanor. Oregon head coach Chip Kelly immediately suspended Masoli for the 2010 football season, his senior year, but allowed him to remain on the team (he still had a redshirt season available).
On June 7, 2010, Masoli was pulled over by Springfield police for a traffic violation. After inspection Masoli was cited for driving with a suspended license, failure to stop, and possession of one ounce or less of marijuana. Two days later he was dismissed from the team for "failure to adhere to obligations previously outlined". Masoli later entered guilty pleas to both the marijuana and failure to stop charges (both non-criminal violations in Oregon).