It's the first game he missed since Sept. 25, 2015, when Royals manager Ned Yost rested several starters against the Cleveland Indians after his team clinched the AL Central title the night before.
With Escobar sitting, the San Diego Padres' Freddy Galvis holds the longest active consecutive games streak. He has played in 255 straight, according to the Elias Sports Bureau. The Atlanta Braves' Freddie Freeman is next on the list with 98 consecutive games played.
Escobar, an All-Star in 2015, has struggled at the plate, hitting just .194 with three home runs and 19 RBIs.
"I was proud about this streak, 421 straight games, that's not easy," Escobar said. "I feel so happy I made that. I understand the situation right now. The team is looking for something different. Ned told me yesterday you have an off-day [Sunday]. I said I don't have any problems, do whatever you want."
Ironman Cal Ripken Jr. holds the record for consecutive games played, with 2,632.
In other moves, Jakob Junis, who had lost his past seven starts, was scheduled to pitch Sunday, but instead went on the disabled list with back tightness. Heath Fillmyer made his first major league start, taking Junis' place.
The Royals purchased the contract of right-hander Glenn Sparkman from Triple-A Omaha. He was 7-3 with a 3.96 ERA in 16 starts between Double-A Northwest Arkansas and the Storm Chasers.
Yost also said veteran right-hander Jason Hammel is being removed from the rotation. Hammel, 2-11 on the season, had allowed 21 earned runs on 28 hits, including five homers, and six walks over 12 innings in losing his last three starts.
"He has an ERA of 6.16 and 32 more hits than innings pitched," Yost said. "He was starting to get super frustrated. It's time to take a step back and reset and give some of the younger guys (a chance). We want to look at some of these young guys in the starting rotation, too. Now is the time."
Burch Smith, a Rule 5 pick, will start Wednesday in Hammel's place against the Twins.
The Associated Press contributed to this report.