Melvin Mora drove in two runs and Miguel Tejada had three hits for the Orioles. Baltimore needed only three innings to take a 5-1 lead against struggling Tampa Bay starter Jae Seo.
Guthrie (2-1) gave up six hits, struck out two and walked none in his second start of the season. Seeking to earn a spot in a rotation that is without injured starters Adam Loewen and Jaret Wright, Guthrie missed the strike zone with only 21 of his 67 pitches.
It was the right-hander's first win in three career starts. He beat Tampa Bay on April 16 by throwing 2 1-3 innings of one-hit relief.
After Guthrie left, Chad Bradford gave up RBI singles to Dioner Navarro and Brendan Harris in the seventh. Harris finished the game 2-4 for the Devil Rays and is now hitting .333 for the season. Last week, Devil Rays manager Joe Maddon finally acknowledged that Harris is Tampa Bay's everyday shortstop. Even though the Devil Rays made it interesting when they cut the Orioles lead to two runs, former Tampa Bay fixture Aubrey Huff doubled in a run in the bottom half to make it 6-3.
Gibbons, who came in batting .188, went 3-for-4. He homered off Jae Kuk Ryu in the eighth and Tejada added an RBI single.
Carlos Pena went 4-for-4 with an RBI for the Devil Rays, who have lost nine of 11 against Baltimore dating to last season. Pena has six hits in his last seven at bats dating back to Sunday's loss to Oakland.
Seo (1-3) allowed five runs and six hits in three innings. He has given up 56 hits, an AL-high 37 runs in only 32 2-3 innings and is toting an unsightly 8.82 ERA.
The South Korean right-hander has failed to make it past the third inning in three of his seven starts, and is 0-4 in eight road starts since July 19.
The Orioles went up 2-0 in the first when Mora hit a two-out, two-run single with the bases loaded. Tampa Bay has been outscored 31-4 in the opening inning this year.
Doubles by Ty Wigginton and Pena produced a run in the Tampa Bay second. Markakis made it 4-1 in the bottom half with his fourth home run, a drive over the right-field scoreboard following a single by Gibbons.
Jay Payton tripled in a run with two outs in the third.
Notes: The Devil Rays called up RHPs Chad Orvella and Tim Corcoran from Triple-A Durham to replace RHPs Ruddy Lugo, who was optioned to Durham after Sunday's game, and Juan Salas, suspended 50 games for testing positive for a performance-enhancing substance. ... Rays LF Carl Crawford made a spectacular diving catch near the corner to rob Ramon Hernandez of a fifth-inning hit. ... Tampa Bay's B.J. Upton extended his hitting streak to a career-high 10 games.
Tyler Hissey contributed to the Associated Press for this story on Rays Digest.