He played college football for the Northwestern Wildcats and was selected by the Denver Broncos in the seventh round of the 2015 NFL draft.

Siemian was part of the Broncos when they won Super Bowl 50, serving as the third-string quarterback behind starter Peyton Manning and backup Brock Osweiler.

[5] At Northwestern University, Siemian majored in Communication Studies and was awarded Academic All-Big Ten Conference honors in 2013 and 2014.

[33] Siemian made his NFL debut in the 2015 season against the Pittsburgh Steelers in Week 15, taking a knee to close out the first half of the 34–27 road loss.

[37] In the 2016 season, following Peyton Manning's retirement and Brock Osweiler signing with the Houston Texans,[38][39] it opened up a competition for the Broncos starting quarterback job between Siemian, veteran Mark Sanchez, and rookie Paxton Lynch.

[41] During the narrow season-opening 21–20 victory over the Panthers, Siemian completed 18-of-26 passes for 178 yards, a touchdown, and two interceptions in his first NFL start.

[45] The following week against the Cincinnati Bengals, he became the first quarterback in NFL history to throw 300 yards and complete four touchdowns with no interceptions in his first career road start in the 29–17 victory.

[48] During Week 12 in a Sunday Night Football game against the Kansas City Chiefs, Siemian threw three touchdowns with no interceptions on 20-of-34 passing for 368 yards.

Although the Broncos ultimately lost 30–27 in overtime, he achieved a quarterback rating of 125.6, the second-best of his career to date when playing in the majority of a game.

Although the Broncos finished the season with a 9–7 record and missed the playoffs, Siemian compiled an 18-10 touchdown-to-interception ratio and an 84.6 passer rating.

[54] On January 23, 2017, he was named as an alternate for the 2017 Pro Bowl, but declined the invitation due to recovery from left shoulder surgery two weeks prior.

[59][60] The following week, Siemian and the Broncos hosted the Dallas Cowboys, led by 2016 Offensive Rookie of the Year Dak Prescott and 2016 leading rusher Ezekiel Elliott.

[64] He came back in the game in the third quarter, but two interceptions and a fumble still proved to be costly as the Broncos lost by a score of 23–10, despite Siemian having a career-high 376 passing yards.

[70] During Week 15 on Thursday Night Football against the Colts, Siemian suffered a shoulder injury in the first quarter of the 25–13 road victory and did not return to the game.

[76] On September 12, 2019, quarterback Sam Darnold was ruled out indefinitely with mononucleosis, and Siemian was named the starter against the Cleveland Browns on Monday Night Football in Week 2.

[77] Siemian suffered an ankle injury on a late hit by Myles Garrett and left the game after completing three of six passes for three yards, and was replaced by third-string quarterback Luke Falk.

[82][83] On November 20, 2020, the New Orleans Saints signed Siemian to their active roster off the Titans' practice squad after an injury to starting quarterback Drew Brees.

[88][89] Siemian made his Saints debut during the 2021 season in a Week 8 against the Tampa Bay Buccaneers after starter Jameis Winston left the game with a torn ACL.

[91] Siemian was named the starter for the next game against the Atlanta Falcons over Taysom Hill who had recently cleared concussion protocol.

[93] Siemian finished the 2021 season (six games played, four as the starter) with 1,154 yards, 11 touchdowns, and three interceptions for a 57.4% completion percentage and a career-high 88.4 passer rating.

[95] Siemian made his Bears debut during a Week 8 49–29 road loss to the Dallas Cowboys, completing his lone pass attempt for five yards.

[106] He made his season debut in the fourth quarter of a Week 13 matchup against the Atlanta Falcons after Tim Boyle was benched.

[108] During a Week 15 30–0 shutout road loss to the Miami Dolphins, Siemian relieved Wilson after he suffered a concussion in the second quarter and completed 14-of-26 passes for 110 yards and two interceptions.

In the game, Siemian completed 27-of-49 passes for 217 yards, a touchdown, and an interception during the narrow 30–28 victory, marking his first win as a starter since 2017.