Santana struck out 10 in eight innings to get his first victory of the season, leading the Minnesota Twins over the Royals 7-3 on Thursday.
In his last seven starts against Kansas City, Santana is 6-0 with a 1.50 ERA. The 2004 Cy Young winner has recorded 115 strikeouts against the Royals in his six-plus seasons, more than any other major league team.
"I felt pretty good today," said Santana (1-3), who had never started 0-3 before. "I was throwing the fastball in and out of the plate and I was able to throw my changeup. It was a nice day."
The Royals, who committed three errors, said Santana's changeup was particularly baffling.
"I was throwing it the whole time," he said. "I knew it was there so I was using it the whole time."
The Twins opened up a 5-0 lead in the second inning and the Royals were quickly in trouble against a pitcher they haven't beaten in almost two years. He allowed seven hits and three runs with one walk.
The only Kansas City starter who did not strike out at least once was Mark Grudzielanek. In one stretch in the fifth and sixth innings, Santana fanned four straight.
"He looked pretty solid," Royals catcher John Buck said. "I faced him last year and he looks just as good."
Angel Berroa homered in the second for Kansas City. It was the Royals' seventh earned run against Santana in his last seven starts and 47 1/3 innings against them.
"We just weren't able to do anything mainly because he was pitching so well," Royals manager Buddy Bell said. "His fastball and his changeup. The biggest part of the day was the five runs early. When you're facing a guy like that, it's a tough situation."
Mark Redman (0-1) lasted 1 2/3 innings in his third start since beginning the season on the disabled list with a knee injury. He was charged with five runs and six hits, with three walks and no strikeouts.
"It was his third start and it wasn't very good today," Bell said. "But for the most part, since we got him back he's been pretty good."
In losing two of three to the Twins, the Royals managed only seven runs. In their last eight series against their AL Central rivals, the Twins have won six and tied two.
"That's a very aggressive-swinging team over there," Twins manager Ron Gardenhire said. "They're like our ballclub. Today Santana was aggressive and he threw the ball great. He was attacking the hitters pretty good."
Lew Ford and Cuddyer had back-to-back singles in the second inning and Ford scored when they executed a double steal and Buck threw the ball into center field.
Cuddyer's homer off reliever Mike Wood made it 6-1 in the third and then Rodriguez scored from third on a fielding error by third baseman Teahen in the sixth.
Berroa's homer was the Royals' first in seven games. With 11 for the year, they still have fewer than any other team in the majors.
- C Joe Mauer, who has hit safely in 14 of 18 games, was out with a sore hamstring. The Twins said he should play on Friday.
- Redmond needs 2 2/3 innings to become the 22nd active left-hander with 1,000 innings.
- Stewart has hit safely in 15 of his 17 games.
- The Twins are 1-2 against left-handers.
- The Royals committed a season-high three errors.
- It was the 24th time Santana has struck out more than nine.