Big Papi drove a 2-0 fastball into the center-field bleachers for a three-run homer that gave the Red Sox a 4-0 lead.
The 39-year-old Ortiz is looking to become the 27th player in major league history with 500 homers.
Earlier on this homestand, Ortiz set a club record by reaching 30 homers in a season for the ninth time with Boston. Hall of Famer Ted Williams owned the previous mark with eight.
It was Ortiz's 32nd homer of the season, and his 59th career against Toronto, most of any opponent.