The loss was the eighth in a row for the D-backs.
The sixth inning started innocently enough for the Angels with Jeff Mathis drawing a walk off closer J.J. Putz. Peter Bourjos followed with a sinking liner to center that Chris Young let bounce past him and roll to the wall for an error, allowing both Mathis and Bourjos to score.
Putz then walked Maicer Izturis and Erick Aybar, who was later caught stealing. That was the only out that Putz recorded before departing following Bobby Abreu's RBI double.
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Bobby Wilson capped the scoring in the inning with a three-run double off Kam Mickolio.
Izturis and Aybar were moved to the top two spots in the Angels' order Wednesday and they delivered going a combined 3-for-6 with a pair of walks.
Mathis continued his hot spring for the Angels going 3-for-4 to raise his average to .400. One day after hitting his first homer of the spring, Torii Hunter added another with a leadoff shot in the second inning.
The D-backs' offense was powered by a pair of two-run homers.
Juan Miranda, who is battling for the first-base job, blasted one in the fourth off starter Jered Weaver, and Justin Upton homered for the second straight game in the fifth off Christian Scholl.
This was the third time this spring that Weaver had faced the D-backs, and the right-hander allowed three runs on three hits in 4 1/3 innings.
"I feel good," Weaver said. "My location's a lot better as Spring Training comes to an end. My off-speed stuff was good. The slider's coming around. Usually it's the last thing to come around. Mechanically, everything's not quite there. But I got my work in, and everything feels good."
Ian Kennedy, who was named Arizona's Opening Day starter Tuesday, allowed three runs (two earned) on eight hits in 3 2/3 innings.
Angels up next: The Angels have their first Cactus League game under the lights on Thursday night, and, fittingly, it's against the reigning World Series champion Giants at Scottsdale Stadium at 7:05 p.m. PT. Dan Haren, 0-2 with a 4.50 ERA, will be making his fourth spring start, looking to build stamina for his season debut in Kansas City. Haren will face left-hander Jonathan Sanchez, with Jordan Walden set to follow Haren as he continues to make his case for the closer's role.
D-backs up next: Aaron Heilman continues his quest to try to win a spot in the rotation when he takes the ball for the D-backs on Thursday against the Dodgers at Camelback Ranch. Chad Billingsley will start for the Dodgers. It is the first time this spring the D-backs will play their division rival. Sam Demel, who seems to have sewn up a bullpen spot by allowing just one run in six innings so far this spring, is also scheduled to pitch.