He played college football for the Arizona State Sun Devils and was selected by the Denver Broncos in the second round of the 2012 NFL draft.

Osweiler first served as the Broncos' starter during their Super Bowl-winning season in 2015 when he relieved an injured Peyton Manning and helped Denver get the top seed in the AFC heading into the postseason, although Manning resumed his starting duties for the playoffs and eventual Super Bowl 50 victory.

After the Super Bowl, Osweiler became the starting quarterback for the Houston Texans, but an unsuccessful 2016 campaign resulted in his tenure lasting only one season.

[1] Osweiler's older brother, Tanner, played college football in the National Association of Intercollegiate Athletics (NAIA) at Montana Tech in Butte.

[22] During the Week 12 overtime loss in the 2013 season, Osweiler was put into the line in an attempt to block the New England Patriots game-winning field-goal, as he was the tallest member of the team at 6'7" (2.01 m) at the time.

[27] Against the Kansas City Chiefs on November 15, 2015, Osweiler took over for Peyton Manning, who was benched after throwing four interceptions and posting a passer rating of 0.0.

[36] On December 15, it was announced that Osweiler would start his fifth consecutive game against the Pittsburgh Steelers despite the fact that Manning had returned to practice.

[38] In Week 16, Osweiler started his sixth consecutive game against the Cincinnati Bengals, completing 27 of 39 attempts for 299 yards and one touchdown in a 20–17 overtime win.

[39][40] In the Broncos' regular-season finale, on January 3, Osweiler was replaced by Manning in the third quarter after throwing two interceptions and fumbling once.

[41] On January 7, 2016, the team announced Osweiler suffered a low-grade strain to the medial collateral ligament of his right knee during a game against the San Diego Chargers.

[43] On February 7, 2016, Osweiler was active as the backup quarterback as the Broncos won Super Bowl 50 over the Carolina Panthers by a score of 24–10.

[44][45] Despite Osweiler not seeing any playing time in the postseason, his 5–2 record as a starter in the 2015 regular season while Manning was sidelined with a foot injury was instrumental in helping Denver capture the top seed in the AFC and earning home field advantage over the New England Patriots in the AFC Championship Game.

During a Week 7 road game against his former team, the Denver Broncos, Osweiler had a total of three fumbles with one lost as the Texans were defeated 27–9.

[52] Due to Savage's injury, Osweiler started the Texans' Wild Card Round playoff game against the Oakland Raiders.

[59] The move allowed Cleveland to absorb some of Osweiler's cap from Houston in exchange for draft picks, one of the first trades of its kind.

[60] On September 2, 2017, Osweiler signed a one-year contract with the Broncos after backup quarterback Paxton Lynch sustained a shoulder injury.

[62] On November 1, it was announced that Osweiler would start the team's Week 9 game against the Philadelphia Eagles in place of the benched Trevor Siemian.

[70][71] On March 23, 2018, Osweiler signed with the Miami Dolphins, reuniting him with his former Broncos offensive coordinator Adam Gase.

[72] During Week 4 of the 2018 season, Osweiler came into the 38–7 loss to the New England Patriots in relief of Ryan Tannehill and threw a touchdown to Frank Gore in the fourth quarter.

[79] In 2024, it was announced that Osweiler would serve as an ambassador for SHARx, a patient advocacy company for uninsured and underinsured Americans.

Those closest to me have experienced the loss of loved ones because the high price of the drugs they needed made access impossible," Osweiler said in a statement announcing his ambassadorship.