He played in Major League Baseball (MLB) for the Cleveland Indians, Baltimore Orioles, Colorado Rockies, Kansas City Royals, and Washington Nationals.

[2] Guthrie attended Ashland High School, where he excelled in basketball, football, baseball, as well as the classroom, where he was class valedictorian.

Guthrie played his freshman season at Brigham Young University before leaving to serve an LDS mission.

Stanford reached the 2001 College World Series final in Omaha, but lost 12–1 in the Championship to the Miami Hurricanes.

[8][10] Guthrie spent most of the 2006 season with the Triple-A Buffalo Bisons, but was twice called up to the MLB to join the Cleveland Indians as a relief pitcher.

After being removed from the 40-man roster following the signing of Trot Nixon and with no remaining Minor League options, he was designated for assignment on January 19, 2007.

[7] Upon joining the team, he requested and was granted permission to wear uniform number 46 from then-executive vice president of baseball operations Mike Flanagan, who had worn it during his playing career with the ballclub.

Through the end of July 2007, Guthrie had a 7–3 record in 17 starts to go with a sparkling 2.89 ERA and a 1.027 WHIP (second only to two-time Cy Young Award winner Johan Santana) albeit only in 124.7 innings of work.

Guthrie's rise to unexpected success in the first half of the season led to consideration for the American League's Rookie of the Year Award.

Guthrie pitched on Opening Day for the Orioles against the New York Yankees, with 48,607 people in attendance at Camden Yards.

[8] On February 6, 2012, Guthrie was traded to the Colorado Rockies for pitchers Matt Lindstrom and Jason Hammel.

[15] Guthrie battled through inconsistency and a mental lapse while pitching in Coors Field, registering an ERA over 8 at home for the Rockies.

In Game 3 of the ALCS against his former team, the Baltimore Orioles, he allowed one run over five innings and got a no decision in the Royals victory.

Guthrie was the first pitcher since Jae Kuk Ryu in 2006 to give up four home runs while pitching fewer than two innings.

[26] On February 3, 2017, Guthrie signed a minor league deal with the Washington Nationals and received an invitation to spring training.

[27] Although he began the 2017 season in the minor leagues despite an impressive showing in spring camp, he was called up on April 8, 2017, to start against the Philadelphia Phillies at Citizens Bank Park.

[28] Making his first start with the Nationals on his 38th birthday, Guthrie struggled immensely as he was removed from the game after getting only two outs in the first inning.

[39][40][41] As announced by the LDS Church on February 1, 2018, Guthrie began a three-year assignment as president of its Texas Houston South Mission in July 2018.