Upton hit a 1-1 fastball from Blue Jays pitcher Edwin Jackson over the left field fence at Rogers Centre on Monday night. Upton's second-inning home run began a seven-run outburst in the Angels' eventual 10-5 victory.
Upton missed the season's first two 1/2 months with a sprained toe.
"I didn't expect a homer in my first at-bat, but I was pretty confident," Upton said. "I prepared myself. I just happened to get a good result."
Upton went 2-for-4 on Monday night. His other hit came later in the second inning.
"You see the impact," Angels outfielder Mike Trout said. "It didn't take him long. One pitch, homer. ... Just to have that bat back, to miss him for 72 games, it's huge. It's huge to get him back."
Upton hit .257 with 30 home runs and 85 RBIs last season. The four-time All-Star is only 13 home runs shy of reaching 300 for his career.