Lackey uncorked an errant pitch in the fifth inning, missing low and inside to Jose Reyes on a 2-2 count. The right-hander immediately clutched his arm, jumping around the mound in pain.
Teammates and manager John Farrell came to the mound before Lackey walked off with Red Sox trainer Rick Jameyson. Lackey was replaced by Alfredo Aceves, who threw ball four to Reyes.
There was no immediate word on the severity of Lackey's injury, or how much time he might miss.
Lackey was pitching in the majors for the first time since Sept. 25, 2011. He sat out last season following Tommy John surgery in November 2011 but looked impressive against Toronto, reaching 94 mph with his fastball and striking out eight batters.
Lackey signed an $82.5 million, five-year contract with Boston in December 2009 after eight seasons with the Angels.
He allowed two runs and five hits in 4 1-3 innings Saturday, throwing 50 of 76 pitches for strikes. The only walk he was charged with was the one to Reyes.
Toronto beat the Red Sox 5-0 behind J.A. Happ.