Thome's three-run shot topped his previous Target Field record blast of 480 feet, which hit off the flag pole beyond right field last September.
"He clocked it, I heard," said Twins manager Ron Gardenhire, who has been battling an illness and was forced to watch the game from the clubhouse.
It was not Thome's longest career home run -- he once hit a 511-foot blast with the Indians that remains the longest in the history of Progressive Field. That home run, on July 3, 1999, also came against the Royals.
Of course, 490 feet is still a pretty impressive blast.
"Ridiculous. I stood up immediately," Twins starter Brian Duensing said. "I knew it was gone when he hit it; I didn't know it was going to go that far.
"That's why it's so fun watching him hit, because you never know when it's going to happen. When he gets them, they're usually big situations or very large home runs. Today was both."
Thome crushed a 3-2 slider from Royals starter Felipe Paulino about halfway up in the second deck. It was the 596th home run of Thome's career putting him just four shy of becoming the eighth player in Major League history to hit 600 or more career homers.
The lefty slugger hit it while still recovering from a sprained left big toe, and at age 40, health issues are the only thing keeping Thome from hitting mammoth home runs on a daily basis.
"I'm not going to win any races," Thome joked about the status of his toe. "I never did anyway. It's coming along good."
Joe Nathan came on in the ninth for his second straight save in the series, the first time since Oct. 2-3, 2009, that Nathan recorded saves in consecutive games.
Nathan has made nine consecutive scoreless appearances, allowing just three hits with seven strikeouts in 8 1/3 innings of work. He sits three saves shy of tying Rick Aguilera on the Twins' all-time list.
Thome's blast gave the Twins just enough offense to support Duensing, who picked up his seventh win of the season. The left-hander went 6 1/3 innings, allowing three runs on seven hits with two strikeouts.
Duensing settled in nicely after opening with three long innings, retiring 10 straight Royals hitters from the third to the second out in the sixth.
"We just said, 'Let's keep going at 'em,'" Duensing said. "I was a little shaky early, and I think part of that was the All-Star break. I threw bullpens when I got back, but being off the mound in a game situation that long ... it took me a little while to get it going."
After Thome handed Duensing a 4-1 lead, he surrendered a two-run blast to Jeff Francoeur in the seventh. Francoeur's home run was his 13th of the season, a 418-foot blast to left. Duensing was taken out after facing one more batter, and the Twins' bullpen retired the Royals in order over the final 2 2/3 innings.
Both teams scored in the first inning in similar fashion before going scoreless until the sixth. Melky Cabrera and Alexi Casilla each doubled with one out, and Alex Gordon and Joe Mauer each drove them in with singles.
With their second straight win and the fourth in five games, the Twins moved to within five games of first place in the American League Central for the first time since April 23. The Twins also are five games under .500 for the first time since they were 9-14 on April 28.
As the first-place Indians head into town on Monday for a four-game series, the Twins have a big opportunity to gain even more ground this week.
"Maybe this momentum will carry us over into the next two series," Thome said. "You don't win every ballgame, but the thing this time of year is you want to win series. And that's what we're trying to do."