Ohtani's first inning solo shot accounted for all the Angels' scoring while Toronto responded with three solo homeruns of their own from Matt Chapman, Danny Jansen and Whit Merrifield to power the Blue Jays to their fourth win in five games.
The stage was set for some Ohtani heroics when the Angels loaded the bases in the ninth but he did not get a chance to bat and was replaced by pinch-hitter Michael Stefanic, who struck out.
Los Angeles manager Phil Niven said Ohtani complained of cramping in his lower legs and would be re-evaluated in the morning.
Ohtani had been scheduled to be on the mound for the opener of the three game set against the Jays but a rainout in Detroit on Wednesday pushed the right-hander into action for the first game of a Thursday doubleheader where he conjured up a complete-game shutout masterpiece.
In the night cap, Ohtani did his damage at the plate slamming two home runs.
As he made his second trip around the Comerica Park bases Ohtani clutched at his side sending a shiver through the Angels dugout as he trotted off into the clubhouse.
"He's fine, completely fine it was just more cramping," Niven assured a pre-game group of mostly Japanese media in the Los Angeles dugout. "I talked to him this morning and he said, "I am 100% and ready to go"."
True to his word the 2021 American League Most Valuable Player took the first pitch from Toronto starter Kevin Gausman and hammered it over the right field wall.
With Ohtani headed to free agency at the end of the season the Angels were widely expected to deal the two-way phenomenon before the August 1 trade deadline rather than let the all-star walk away with nothing in return.
But Ohtani is having another MVP season leading the major leagues in homers and an impressive 9-5 pitching record that is making it almost impossible for the Angels to trade him as they make a push for the postseason.
The Angels have not appeared in the playoffs since 2014 but with just two losses in their last 10 are in the thick of the American League wildcard chase and trading away the game's best player would be viewed by fans as throwing in the towel.
Also Angels owner Arturo Moreno would not relish the prospect of becoming the modern day version of Harry Frazee, the Boston Red Sox owner who traded baseball's most iconic figure, legendary two-way star Babe Ruth, to the New York Yankees.