Guerrero's gargantuan blast came during the bottom of the eighth inning in the 11-7 victory on Wednesday at Rogers Centre in Toronto.
Toronto opened the game with a 2-0 lead after getting a two-run homer from Randal Grichuk in the bottom of the first frame. The Blue Jays pushed the lead to 3-0 in the second frame, before Gary Sanchez hit a solo homer for the Yankees in the top of the fourth inning.
The Yankees stole the momentum with a three-run fifth frame, earning a 4-3 lead. Guerrero then tied the score with an RBI single in the bottom of the fifth inning. But the spark didn't stay lit for long.
DJ LeMahieu gave New York a 7-4 lead with a three-run shot in the sixth inning. Teoscar Hernandez got the Blue Jays back to within one run with an RBI double in the bottom of the next inning.
The Blue Jays blanked the Yankees in the top of the eighth inning before their bats came alive in the bottom of the frame. Freddy Galvis grounded out to begin the bottom of the inning. Danny Jansen singled before Yankees reliever Zack Britton walked Lourdes Gurriel Jr.
The Yankees left-handed pitcher then settled in against Guerrero. Britton began the exchange with a sinker for a ball. Guerrero then fouled off another Britton sinker to even the count at 1-1.
Britton issued another of his trademark sinkers for his third offering to Guerrero. The superstar rookie belted the low offering for a 434-foot homer over the center field fence. The blast had an exit velocity of 110 mph and a launch angle of 18 degrees, according to Statcast.
Britton forced Justin Smoak to ground out in the next exchange, before being pulled for Luis Cessa. Cessa immediately surrendered back-to-back home runs to Grichuk and Brandon Drury for the final runs of the game.
Guerrero was 2-for-4 with three RBIs, three runs scored and a walk in the win. He is now hitting .256 with seven home runs and 16 RBIs on the season. Grichuk was 2-for-4 with three RBIs, three runs scored, two home runs and a strikeout for the Blue Jays.
The Blue Jays host the Yankees in the series finale at 7:07 p.m. Thursday in Toronto.