Guthrie was the ace of the Stanford University staff and formed a battery with Ryan Garko. He pitched in the regionals that season against MAAC champion Marist College in the first game and won 5-3. His team made it all the way to the World Series final in Omaha, but lost 12-1 in the Championship to the Miami Hurricanes.
Guthrie was claimed off waivers by the Baltimore Orioles on January 29, 2007. 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. After starting the year in the Baltimore Orioles' bullpen and then moving into the starting rotation, Guthrie enjoyed a breakout year in 2007, becoming one of the best and most consistent pitchers in the American League. Through June 21 that year, he ranked 2nd in ERA and allowing more than two earned runs in just 1 out of 10 starts. He was also first in the AL in WHIP.
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 2-time Cy Young award winner Johan Santana), albeit in only 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.
On July 20, 2012, Guthrie was traded to the Royals for left-handed starter Jonathan Sanchez. He proved to be the Royals best pitcher in the second half of the season, posting a record of 5-3 with a 3.16 ERA in 14 starts. On November 20, Guthrie inked a 3-year, $25 million deal with the Royals through 2015. Guthrie will earn $5 million in 2013, $11 million in 2014, and $9 million in the contract's final year.