On September 29, 2014, Bills head coach Doug Marrone named Orton starting quarterback of the then 2–2 Bills.
He was a Heisman Trophy hopeful until a late 4th quarter Orton fumble was run back for a Wisconsin touchdown against the undefeated 12th ranked Wisconsin Badgers, giving the 5th ranked Purdue its first of several losses that season.
Later that season, he received multiple injuries, in consecutive games against Michigan and Northwestern forcing him to lose his starting position for a month. Orton makes a cameo in NCAA Football 2006, where he says, "EA Sports, it's in the game", along with Derek Anderson in the game's introduction.
Orton tied former Purdue quarterback Drew Brees' record for number of passing yards in a game (522 vs.
Indiana Hoosiers), and is the only Purdue quarterback to start four consecutive bowl games (Brees and Mark Herrmann started three straight).
Orton started in the 2001, '02 and '04 Sun Bowl, and the 2003 Capital One Bowl.
During his undergrad years at Purdue, Orton was a member of the Pi Kappa Alpha fraternity.After throwing 3 interceptions versus the Arizona Cardinals on December 12 and with the Broncos eliminated from the playoffs, Orton was replaced by Tim Tebow for the final three games of the 2010 season.In 2011, he again began the season as a starter, but he was replaced by Tebow again after a disappointing start to the season.The outcome of this game, for the Chicago Bears, did not have any effect on their post-season hopes.The Bears had already clinched the NFC North championship and a first-round bye in the 2005–06 playoffs with their Week 16 victory over the Green Bay Packers.Grossman then started for the Bears in their only post-season game. Overall, the Bears had a record of 10–5 in games that Orton started, including an eight-game winning streak after a 1–3 start.