Guthrie is also hoping a matchup with the Baltimore Orioles will help him end a six-game winless stretch Friday night.
The Royals (20-20) won three in a row, matching their second-longest streak of the season, before falling 2-1 in Thursday's series opener. They scored a combined 17 runs in their previous three games.
Guthrie (2-2, 4.80 ERA) will try to lead Kansas City to its seventh win in 10 contests when he makes his fourth career start against his former club. The right-hander spent five years with the Orioles (21-18) before being traded to Colorado before the 2012 season.
Guthrie is 2-0 with a 1.89 ERA against Baltimore. He gave up two runs over seven innings at Camden Yards on April 26 and did not get a decision in a 3-2 loss.
"It's always enjoyable to compete against friends and former teammates," Guthrie told the Royals' official website. "At the end of the day, once you throw a pitch, it's more or less the same as any start."
Guthrie, however, is coming off his worst outing of the season and has struggled of late. He was charged with seven runs in 4 2-3 innings in Seattle on Sunday but was bailed out when his teammates rallied for a 9-7 victory.
Guthrie has gone 0-2 with a 5.21 ERA in his last six starts.
Baltimore snapped a season high-tying four-game skid Thursday, with Nelson Cruz providing both runs with his 12th homer of the season.
Chris Tillman (3-2, 3.97) will try to help the Orioles build on that win while earning his first victory in four starts this month. The right-hander has given up three runs in each of his last three outings but has made it past the fifth inning only once, going 0-1 with a 5.17 ERA.
Tillman allowed four hits and walked a season-high five in five innings of a 5-2 loss to Houston on Sunday.
"He just hasn't quite gotten in sync consistently. And he will," manager Buck Showalter told the team's website. "Fortunately for us, he kept us engaged in the game at 3-2. I take that as a positive. A lot of guys wouldn't, and I think that's a sign of his maturity."
Tillman earned a 5-3 win in his only start against Kansas City last season, giving up three runs and five hits over six innings May 8. He was 0-2 with a 13.50 ERA in his previous two matchups.
Mike Moustakas, 3 for 6 against Tillman in his career, broke out of a 3-for-27 slump with two doubles and three RBIs in a 3-2 win over Colorado on Wednesday. He did not play Thursday but is expected to return to the lineup Friday.
Salvador Perez, batting .371 with three homers in his last 16 games, is 1 for 2 off of Tillman.
Cruz, Delmon Young, Chris Davis, J.J. Hardy, Adam Jones and Manny Machado are a combined 11 for 88 (.125) against Guthrie. Nick Markakis is 3 for 8.
Markakis, who snapped an 0-for-14 slump and had three singles Thursday, has hit .486 in his last nine games against the Royals and .444 in his past eight in Kansas City.