Santana (9-7) had an embarrassing 8.05 ERA in his first nine career starts at Rangers Ballpark, but the only damage Texas could do against him this time were two solo homers.
Jeff Mathis homered for the Angels, who won their first game in four and moved back within six games of AL West-leading Texas.
Rangers starter Scott Feldman (5-9) took the loss.
In New York, Jose Guillen homered and drove in two runs as Kansas City beat New York.
Rick Ankiel also had a pair of RBIs as Kansas City pounded New York's spot starter Sergio Mitre.
Royals starter Kyle Davies (5-6) served up a pair of home runs but otherwise held the hot-hitting Yankees in check on a sweltering afternoon in the Bronx. Davies survived 5 1-3 innings to win for the first time since May.
Alex Rodriguez remained stuck on 599 career home runs for the second straight day. He flew out in the first, singled in the fourth and grounded out in the fifth.
In Oakland, Jack Cust hit two home runs as Oakland cruised past Chicago.
Kurt Suzuki, who agreed terms on a four-year deal with the A's a day earlier, added a homer of his own.
Chicago starter Freddy Garcia (9-4) lasted a career-low 1 2-3 innings and had his personal six-game winning streak snapped. He gave up five runs and walked three in his brief appearance.
Oakland's Vin Mazzaro (6-2) ceded a two-run homer in the second, while striking out five to take the win.
In Detroit, Jose Bautista drove in a pair of runs to help Toronto to a win over Detroit, who lost Magglio Ordonez to a fractured ankle.
Ordonez broke his ankle sliding into home plate and is expected to miss 6-to-8 weeks. It was the second major injury this week for the Tigers, who lost third baseman Brandon Inge to a broken left hand.
Carlos Guillen also left the game with a calf injury.
Toronto starter Shaun Marcum (9-4) allowed two runs in 5 2-3 innings. Kevin Gregg pitched the ninth for his 22nd save in 26 tries.
Tigers rookie Rick Porcello (4-8) dropped to 0-4 in his past six starts, a stretch that included a trip to the minors. He allowed three runs and four walks in six innings.
In Cleveland, David Price held it together after a rocky start to guide Tampa Bay to its first win in Cleveland in 19 attempts.
Price (13-5) trailed 3-0 in the second, but allowed only three hits in seven-plus innings and tied C.C. Sabathia for the league lead in wins.
A three-run homer from Ben Zobrist and a solo shot from Carlos Pena helped the Rays get their first win at the Indians since 2005.
In Seattle, Michael Saunders hit a two-run homer in the sixth to put Seattle on course for victory over Boston.
Boston starter Jon Lester (11-5) was on course for a no-hitter early in the sixth before Saunders' shot, and the Mariners added three more runs in the eighth.
It was only the second homer Lester had given up to a left-handed hitter all season.
Seattle's Chris Seddon (1-0) got his first career win.
In Baltimore, Delmon Young went 4-for-4 with a homer and three RBIs to power Minnesota past Baltimore.
The four hits tied a career high for Young, who is batting .429 with four homers and 22 RBIs in July.
The Twins received an impressive pitching performance from Scott Baker (8-9), who allowed two runs, struck out eight and walked just one in seven innings. He is 5-0 with a 2.53 ERA in seven career outings against the Orioles.
Minnesota took a 3-2 lead on Young's two-run drive in the fifth inning before pulling away against the Baltimore bullpen.
