Santana pitched well enough to win and the Twins rallied to beat the Tampa Bay Devil Rays 6-4 for their seventh straight victory.
Michael Cuddyer drove in two runs for Minnesota, which won for the 19th time in its past 24 games and improved to a major league-best 37-11 at home. The Twins have won 20 of their last 21 at the Metrodome.
Minnesota, just 17-29 on the road, will begin a six-game trip Friday in Cleveland. The Twins will play three games versus the Indians and three more against the Chicago White Sox. Minnesota has moved to within four games of AL wild-card leader Chicago.
"This time of year, you have to win series," Twins manager Ron Gardenhire said. "We have to get back winning series on the road. We've played hard on the road. We just haven't had the results."
Travis Lee and Jorge Cantu hit solo home runs for Tampa Bay, which lost its season-worst seventh in a row overall and 12th straight to Minnesota, the most in franchise history against an opponent. The Devil Rays haven't beat the Twins since June 3, 2004.
"We're pressing a little bit," said Tampa Bay manager Joe Maddon, whose team finished 0-7 on its road trip coming out of the All-Star break, with the other three losses coming to the Los Angeles Angels. "I want to get home and see how we do. We've played better at home."
Santana (11-5) allowed three runs and six hits with a season-high four walks in six innings. The left-hander struck out seven to increase his season total to 152, best in the majors.
"Whatever it takes, as long as win games and keep winning and winning and winning," he said.
Although Santana wasn't very sharp, he improved to 11-0 in his past 17 starts at the Metrodome. The Twins' ace hasn't lost at home since Oakland beat Minnesota 2-1 on Aug. 1, 2005.
"It was a battle for him today," Gardenhire said. "I don't think he had his best pitches, but he battled his tail off and our guys picked him up."
Joe Nathan worked the ninth to earn his 18th save in 19 chances.
James Shields (4-4) allowed five runs and eight hits in 4 1/3 innings for the Devil Rays. The rookie right-hander is 0-4 in his past five starts.
"I felt pretty good until the last inning," Shields said. "I'm not worried. I just have to keep getting after them."
After Santana's wildness helped the Devil Rays score two runs in the top of the fifth to take a 3-1 lead, the Twins responded by batting around and scoring four runs in the bottom half.
Jason Tyner hit an RBI single and later came home on a wild pitch to tie it. Joe Mauer and Cuddyer had run-scoring singles to help Minnesota build a 5-3 lead. Shields allowed four hits and two walks against seven batters in the inning before he was relieved by Chad Harville. The only out Shields recorded was on Luis Castillo's sacrifice bunt.
"Every one of their guys is a scrappy hitter," Shields said. "They don't go for the home run, just one hit at a time. That's what they did to us the whole series."
After watching the Twins give him the lead, Santana came out and pitched a perfect sixth.
"He knows what to do with a lead," Gardenhire said. "I'll tell you that."
Castillo added an RBI single in the bottom half to give the Twins a 6-3 lead.
Cantu homered off Juan Rincon in the eighth. It was the first homer Rincon allowed since July 18, 2005, against Baltimore's Miguel Tejada.
The Twins' rally allowed Santana to win even though he struggled with his command. The 2004 AL Cy Young Award winner issued three walks in the fifth, including a free pass to Carl Crawford that loaded the bases with two outs. Rocco Baldelli followed with a two-run single.
The Twins tied it at 1 in the fourth thanks to some creative base running by Nick Punto. Punto led off the inning with a single and took off to steal second base with one out. The Devil Rays pitched out, and catcher Josh Paul's throw to shortstop Julio Lugo easily beat Punto to the bag.
Punto, however, stopped several feet short of the base and was able to dodge Lugo's tag attempt and dive into second. Cuddyer then hit an RBI double to drive in Punto.
"He kind of stopped and avoided the tag," Lugo said. "He got lucky. Everything's going his way right now."
Lee put the Devil Rays up 1-0 when he led off the third with a 407-foot home run to right-center.
- Castillo extended his hitting streak to a season-high 14 games, and Punto stretched his to 13, which ties his career high.
- Mauer made his 10th start of the season as the designated hitter.
- Lee hadn't homered since April 13 coming into the series, but he hit two in the four-game set.
- The Devil Rays suffered their sixth winless road trip of two or more cities in team history.