Teoscar Hernández had his first career five-hit game and Bo Bichette added a solo home run, his 24th, as the surging Blue Jays improved to 12-1 in September.
The AL East-leading Rays lost for the fourth time in five games and are 5-7 this month after going 21-6 in August.
Facing left-hander Adam Conley in the sixth, Guerrero lined a 3-1 pitch down the left-field line, breaking a tie with Angels two-way star Shohei Ohtani for most home runs in the big leagues.
In doing so, Guerrero also eclipsed the single-season high set by his Hall of Fame father with Montreal in 2000.
Toronto leads the majors with 232 home runs this year.
Rays center fielder Kevin Kiermaier climbed the wall to make a spectacular catch on Lourdes Gurriel Jr.’s deep drive in the seventh.
Gurriel had three hits and two RBIs, and Breyvic Valera added three hits and drove in three runs as the Blue Jays maintained their position atop the crowded AL wild-card chase. Toronto began the day tied with Boston, but the Blue Jays have played two fewer games than the Red Sox.
With 17 hits in all, it was another offensive outburst by the Blue Jays, who scored 22 runs against Baltimore on Sunday. That came one day after Toronto put up 22 runs in a doubleheader against the Orioles.
Manoah (6-2) allowed just one hit, walked none and struck out 10, one shy of his career best. He won for the first time since beating the Angels on Aug. 11, snapping a five-start winless streak.
The rookie right-hander was perfect until Joey Wendle singled on a two-strike fastball with two outs in the fifth. Manoah responded by striking out Taylor Walls to end the inning.
Rays outfielder Austin Meadows hit a home run off Trevor Richards in the ninth, his 25th.
Tampa Bay left-hander Ryan Yarbrough (8-5) allowed seven runs and 10 hits in 2 1/3 innings.
Rays manager Kevin Cash said INF Brandon Lowe was held out of the starting lineup because his legs are “beat up.” Cash said Lowe was available off the bench.
The Blue Jays recalled LHP Ryan Borucki from Triple-A Buffalo and optioned RHP Trent Thornton to their top farm club.
Blue Jays RHP José Berríos (11-7, 3.52 ERA) faces Rays RHP Drew Rasmussen (2-1, 3.25) on Tuesday. Berríos is 0-2 with a 7.15 ERA in four career meetings with the Rays, but hasn’t faced them since May 2019 with Minnesota.