"Tonight, in all facets of the game, the Blue Jays just dominated us,'' Rays center fielder Kevin Kiermaier said.
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.
"We hate losing games, don't get me wrong,'' Kiermaier said, "but no one is hanging their head or slouching their shoulders after the last four or five days.''
Facing left-hander Adam Conley in the sixth, Guerrero lined a 3-1 pitch down the left-field line, breaking a tie with Ohtani, the Angels' two-way star, for most home runs in the big leagues.
He became the majors' outright home run leader for the first time since June 27 and for the 15th day this season. Ohtani has led MLB outright in home runs at the end of 79 days this season.
Guerrero's homer had a 15.4-degree launch angle, the third-lowest launch angle on any home run this season in the big leagues.
"I think the third baseman jumped,'' Blue Jays manager Charlie Montoyo said. "I thought it was going to hit the wall -- there was no way it was going out. When it went out I went, 'Oh my God.' Not many people can do that.''
With his homer, Guerrero also eclipsed the single-season high set by his dad with Montreal in 2000. The drive came off the bat at 113.9 mph and was projected at 356 feet.
Toronto leads the majors with 232 home runs this year.
Twenty-eight of Guerrero's 45 home runs have come in home games, most in the majors this season (Ohtani is second with 25) and tied with George Bell in 1987 for the third most in Blue Jays history.
"We know what's at stake, we know what we're playing for,'' Manoah said. "Huge series right here, got to get as many as we can and keep it going.''
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.
"After the third or fourth inning, the game was basically over,'' Tampa Bay manager Kevin Cash said.
Making heavy use of his slider, Manoah (6-2) allowed just one hit, walked none and struck out 10, one shy of his career best.
"That slider was nasty tonight against some good left-handed hitters,'' Montoyo said.
Information from ESPN Stats & Information and The Associated Press was used in this report.