The 20-year-old phenom hit the 402-foot shot in the top of the ninth inning of the 9-2 triumph Tuesday at Kauffman Stadium in Kansas City, Mo.
"He's getting hot now," Blue Jays manager Charlie Montoyo told reporters. "I knew that was going to happen.
"He's seeing the ball better, having better at-bats, because he wasn't doing that early, but he was still getting hits, because he's that good ... Now, he's getting really hot and hitting the ball hard."
Lourdes Gurriel Jr. gave the Jays their initial lead with an RBI single in the top of the first frame. Guerrero Jr. plated Randal Grichuk on another RBI single in the same frame for a 2-0 edge.
Freddy Galvis singled in Brandon Drury and Danny Jansen for a 4-0 lead in the fifth frame, before the Royals finally got on the scoreboard in the bottom of the eighth inning. Meibrys Viloria hit an RBI double for the Royals' first run.
Grichuk stepped up to the plate with the bases loaded in the ninth frame and reached base on a fielding error, resulting in the Jays' fifth run. Guerrero stepped into the box as the next batter of the inning. He took a Josh Staumont fastball for a called strike before smashing Staumont's next offering over the left field fence for his 11th homer of the season.
Guerrero's grand slam had an exit velocity of 104 mph and left the field in 5.7 seconds, according to Statcast.
Cheslor Cuthbert plated the final run of the game for the Royals with an RBI double in the bottom of the inning.
Guerrero was 2-for-5 with five RBIs, a run scored and a strikeout in Tuesday's victory. He is now hitting .261 with 11 home runs and 43 RBIs in 78 games this season for the Blue Jays. Blue Jays starter Sean Reid-Foley earned his first win of the season, allowing four hits in five scoreless innings.
Toronto battles Kansas City at 1:15 p.m. EDT Wednesday at Kauffman Stadium.