Facing a 3-1 count against Chicago White Sox right-hander Carson Fulmer, Ramirez sent a pitch over the right field wall with two outs in the first inning. The grand slam gave the Indians a 4-0 lead.
Later in the top of the third, Ramirez belted a three-run home run off Hector Santiago to push the Indians' lead to 8-0 as Cleveland pushes for an American League wild-card spot.
The Indians activated Ramirez from the 10-day injured list before the game. The All-Star third baseman, who turned 27 last week, suffered a broken bone in his right hand Aug. 24 against the Kansas City Royals. He underwent surgery two days later.
"I'm not 100 percent on my wrist, but still I feel a big improvement and I'm ready to play," Ramirez told reporters through a translator before the game.
Ramirez, a two-time All-Star, had a .254 batting average with 20 homers and 75 RBIs in his first 126 games this season. Before his injury, he was hitting .320 with 15 home runs and 45 RBIs in 46 games in July and August.
The Indians were a half-game back of the Tampa Bay Rays for the second wild card entering Tuesday's slate of games.