The solo shot came in the top of the fifth inning of the 7-1 win early Thursday at Progressive Field in Cleveland. The Tigers also won the first game of the double-header late Wednesday.
"He's getting healthier and he's starting to lock in his timing," Tigers manager A.J. Hinch told reporters, when asked about Cabrera. "He's starting to stay disciplined to his approach.
"Even a polished veteran hitter, such an accomplished hitter like him, needs a tweak every now and then."
The Tigers carried a 3-1 lead into the fifth frame of the second game of the twin bill. Jonathan Schoop singled in the first at-bat of the inning, but was out when Jeimer Candelario grounded into a double play. Cabrera the stepped to the plate.
The veteran designated hitter swung and missed at a 92.9-mph fastball from Indians relief pitcher Nick Wittgren. He then smacked Wittgren's second pitch over the outfield fence for his seventh home run of the season and the 494th of his career.
Tigers center fielder Derek Hill his team a 6-1 lead with a two-run single in the sixth inning. First baseman Jonathan Schoop then brought in the final run with an RBI single.
Tigers pitcher Wily Peralta allowed three hits and one run in five innings to improve to 1-1 this season.
Cabrera, 38, entered the game tied with Gehrig and Fred McGriff for 28th all-time. The two-time MVP and 11-time All-Star needs eight homers to tie Eddie Murray for No. 27 on the all-time list.
Cabrera is hitting a career-low .240 with 31 RBIs, in addition to his seven homers. The 19-year veteran has a career .311 batting average. His 2,919 career hits rank 41st in MLB history.
The Tigers (36-45) host the Chicago White Sox at 7:10 p.m. EDT Friday at Comerica Park in Detroit.