Mitchell graduated from Katy High School in Katy, Texas in 2008. As a senior in 2007, he passed for 2,451 yards and 37 touchdowns with only four interceptions. He led Katy to a 16–0 undefeated season and a state championship. He was named to the Houston Chronicle’s Houston Top 110. Mitchell chose to attend SMU over an offer from Hawaii. Mitchell was also recruited by Eastern Washington.

As a sophomore in 2009, he started SMU’s first seven games before suffering an injury and being replaced by freshman Kyle Padron. Mitchell completed 56 percent of his passes for 1,725 yards, 12 touchdowns and 10 interceptions, for a passing efficiency rating of 117.9. However, SMU was 3–4 in those seven games before winning five of its last six to finish 8–5.

As a junior in 2010, Mitchell transferred to Eastern Washington University, which had previously recruited Mitchell out of high school. He helped lead EWU to victory in the FCS Championship Game, a 20–19 come-from-behind victory over the University of Delaware, the school’s first national championship in football. He was named the game’s Most Outstanding Player after throwing three touchdown passes in the final 16 minutes of the game and had 302 total passing yards in the game as well.

In the 2011 season, Mitchell led the FCS in four statistical categories, including passing yards (4,009) and touchdown passes (33) on his way to breaking four school records. He broke EWU’s record for single season passing yards with 4,009, which ranks 17th in FCS history and fifth in Big Sky Conference history. Mitchell went on to win the Walter Payton Award as the best offensive player in the FCS and was also named the 2011 Big Sky Conference Offensive Player of the Year. Mitchell was also named to seven All-America teams this season, earning first team honors on six of them. He was the top quarterback on teams selected by The Sports Network, American Football Coaches Association, Walter Camp, Associated Press, Phil Steele Publications and Beyond Sports College Network.

Mitchell went undrafted in the 2012 NFL Draft. On April 30, 2012, the Calgary Stampeders of the Canadian Football League signed Mitchell to a free agent contract. Mitchell saw limited playing time in the 2012 CFL season, playing as a 3rd-string backup behind Drew Tate and Kevin Glenn and ahead of Brad Sinopoli. He began the 2013 CFL season as the 3rd-string QB. Mitchell came on in the third-quarter after Kevin Glenn left with an injury (Drew Tate was already injured) and helped the Stamps to overcome a 24-point deficit to defeat the Alouettes on July 20, 2013.

In his first CFL start, on July 26, 2013, Mitchell completed 29 of 33 attempts while passing for 376 yards, in a big win over the Winnipeg Blue Bombers. Mitchell won the Gibson’s Finest Offensive Player of the Week for this performance. The 2013 season proved to be a breakout season for Mitchell. He played significant time at quarterback in 5 of the games, and appeared in another 7 games. His completion percentage was an impressive 69.6%, throwing for 1,156 yards with 10 touchdowns and only 3 interceptions: a quarterback rating of 111.2.

On January 14, 2014, Mitchell signed a contract extension with the Stampeders, which was set to keep him in Calgary through 2016. On June 14, 2014, Mitchell began the 2014 pre season with the Calgary Stampeders. The first week/game he played one quarter and ended the night with 76 passing yards in a 23–20 victory over the Winnipeg Blue Bombers. On June 20, 2014 in the second week of pre season against the BC Lions Mitchell threw for 100 yards, 0 TD’S and 2 INT. On June 23, he was named the starting QB for their week 1 game against the Montreal Alouettes. On opening day, Bo Levi Mitchell gave the Calgary Stampeders their first win of the season 29–8 against the Montreal Alouettes. Mitchell had 313 passing yards and 2 touchdowns and 0 interceptions. On Thursday, July 24, 2014, Bo Levi Mitchell tied Jeff Garcia’s CFL record for consecutive career starts, going 7–0, with a 26–22 victory over the Edmonton Eskimos. On November 23, 2014, in his first playoff start, Mitchell led the Stampeders to a victory in the Western Final over division rival Edmonton Eskimos, earning them a berth in the 2014 Grey Cup. He and the Calgary Stampeders would go on to defeat the Hamilton Tiger-Cats 20–16 in the 102nd Grey Cup. Mitchell was named Grey Cup MVP. On March 3, 2015, his 25th birthday, Mitchell signed an extension with the Stampeders to keep him in Calgary through the 2018 season.

Mitchell continued to improve in the 2016 season setting career highs in passing attempts, completions, yards and touchdowns. Mitchell started in 17 games in the regular season before being rested for the final game of the season after leading the Stamps to a 15–1–1 record, including a 15-game unbeaten streak which set a CFL record for most consecutive wins by a starting quarterback. Mitchell and the Stampeders dismantled the BC Lions in the West Division Final, winning 42–15 and advancing to the Grey Cup in the process. Prior to the Grey Cup game Mitchell was named the CFL’s Most Outstanding Player. Mitchell and the Stampeders played in three consecutive Grey Cup matches starting in 2016, losing the first two (104th Grey Cup and 105th Grey Cup) before winning the 106th Grey Cup 27-16 over the Ottawa Redblacks. Similar to the 2014 season, Mitchell was named the CFL’s Most Outstanding Player and Grey Cup Most Valuable Player. In 2018 he became the fastest quarterback to 60 wins in CFL history, only taking 72 starts to do so, surpassing Ken Ploen who had previously held the record with 60 wins, with 78 starts. Shortly after winning the Grey Cup Mitchell announced that he would be pursuing NFL opportunities before signing another CFL contract.

Mitchell was set to become a free agent in February 2019, having decided to explore NFL opportunities before re-signing with the Calgary Stampeders organization. He attended his first NFL workout on December 5, 2018 with the Minnesota Vikings, with more than five teams inviting him to a workout and ten inquiring about him in the days and weeks subsequent to his first NFL workout. Mitchell later said he decided he would reject an offer from the Vikings because a team official told him they did not want a quarterback controversy. Mitchell also worked out for the Denver Broncos, Jacksonville Jaguars, Buffalo Bills, New York Giants and Chicago Bears. During the 2019 CFL free agency, Mitchell officially became a free agent and had not yet been signed by an NFL team with CFL teams beginning to offer contracts such as the Toronto Argonauts, the Edmonton Eskimos and the Saskatchewan Roughriders with the minimum contract being offered to Mitchell being rumored around $750,000 per season.

On February 12, 2019, Mitchell re-signed with the Calgary Stampeders, in a four-year deal worth $2.8 million. Mitchell suffered a pectoral injury in Week 3 and was subsequently placed on the six-game injured reserve list. By mid-August Mitchell was appearing to be close to a return, however, he was placed back on the 6-game injured reserve list on August 16, 2019 after suffering a minor setback. He was taken off the 6-game injured reserve list 13 days later, on August 29, 2019 and made his return to the starting lineup that weekend.