Minnesota then walked to victory thanks to some surprise command issues from Kansas City's bullpen.
Three runs in Minnesota's decisive seventh inning scored on bases-loaded walks, and the Twins won their season opener for the first time since 2008.
"Just keep grinding out at-bats," Minnesota first baseman Joe Mauer said. "Doing the little things to win ballgames. That's what we've been preaching all spring."
Santana (1-0) allowed just two hits -- one a solo homer by Mike Moustakas -- and had three strikeouts in his second career Opening Day start.
"It's real nice, especially with the way we did everything," Santana said. "Hitting, defense, pitching was good. So everything was good today."
Matt Strahm (0-1) gave up four runs, two hits and two walks in relief of Kansas City starter Danny Duffy.
Duffy left after striking out eight over six strong innings, surrendering three hits, including the solo homer to Sano. Duffy was making his first career Opening Day start.
"I felt like I threw the ball pretty well," Duffy said. "I got to be more efficient. I have no business walking three people with the stuff that I have. I shouldn't have created that situation. That's on me. With my stuff, I have no business picking apart, trying to nitpick. But for a first start of the year, I felt pretty solid."
A tidy affair between the two starters turned into a romp by Minnesota.
Santana walked the leadoff hitter to start the seventh and then got three straight strikeouts to end his day.
Jorge Polanco started the bottom of the seventh with a single. Max Kepler tried to sacrifice Polanco to second but was safe on the bunt down the first-base line after an umpire review showed he beat the throw.
Eddie Rosario followed with a sacrifice bunt and Brian Dozier was intentionally walked to load the bases.
"We weren't going to take any chances with Dozier," Royals manager Ned Yost said. "We did have the matchup that we liked, command evaded us from that point."
Strahm couldn't find the plate and walked Robbie Grossman with the bases loaded. Reliever Peter Moylan struck out Byron Buxton, but Travis Wood entered and walked Mauer and Sano to force in two more runs.
Jason Castro followed with a two-run single and Polanco drove in another run with his second hit of the inning.
"That was unacceptable what happened," Wood said. "You can't come in there and walk two and then give up two hits like that with a game being that close."
Castro collected two hits and a walk in his first game for the Twins.
"He had a heck of a day," Minnesota manager Paul Molitor said. "We're kind of watching some of our game planning on certain hitters and how he was able to help Ervin and then a couple of relievers execute. And then offensively, to get our first hit, took a walk, did a nice job on delivering a big hit there to kind of blow that inning open for us."
Strahm is in his second season after pitching in 21 games as a rookie last year. Moylan is in his second year with Kansas City and Wood was added in the offseason. The Royals had the fifth-best bullpen ERA last season at 3.45 after finishing second in 2015 with a 2.72 ERA.
"Temperature was pretty cool out there, which at times makes it tough to control the ball," Yost said. "But Duffy and Santana had no problem with it. They both were excellent. Both starting pitchers were tremendous. Just one of those things where we couldn't command it."
NOTES: The Twins recognized the late Yordano Ventura and Yorman Landa. Ventura and Landa both died in car crashes in the offseason. Landa was killed in Venezuela and Ventura in the Dominican Republic. The Twins had a patch with YL on their uniform and Kansas City will wear an "Ace 30" patch all season. ... 1B Joe Mauer started his 13th Opening Day for Minnesota, tying him with Harmon Killebrew for the most in club history (since 1961). He is one of three current players with 13-plus seasons with one team, with Mets 3B David Wright and Cardinals C Yadier Molina the others. ... The Royals opened the season in Minnesota for the first time in their 49-year history. They had hosted the Twins four times previously for Opening Day. ... Monday marked the second time the Twins have opened the season at Target Field since the stadium opened in 2010.