Ramirez's 412-foot rip helped the Indians to a 5-3 victory Wednesday in Cleveland.
"I really understand the nature of the game," Ramirez told reporters, according to MLB.com. "It has ups and downs. Fortunately, I have a little bit of a track record, where I know what I've done, what I can accomplish, and that's what I try to remember. And remember, it's a long season. It just started."
Jose Abreu drew first blood with a solo shot in the top of the third inning for the White Sox. The Indians then pulled ahead with a big fourth inning. Leonys Martin grounded into a force out, scoring Carlos Santana to tie the score at 1-1.
Tyler Naquin then plated Carlos Gonzalez and Martin with an RBI single in the same inning, giving Cleveland a 3-1 advantage.
But the White Sox tied it in the seventh frame. Right fielder Ryan Cordell singled in Charlie Tilson and Tim Anderson to make the score 3-3. Neither team scored a run in the eighth frame, setting the stage for a dramatic ninth inning.
Indians reliever Brad Hand sat the White Sox hitters down in order in the top of the final frame. Jordan Luplow began the bottom of the ninth inning with a strikeout. White Sox reliever Jace Fry then surrendered a single to Francisco Lindor, putting the go-ahead run on first base. Jason Kipnis struck out in the next at-bat, prompting Ramirez to walk to the plate.
The White Sox yanked the left-handed Fry for the right-handed Kelvin Herrera to face the Indians slugger. Ramirez worked a 3-1 count against the White Sox reliever before settling in for Herrera's fifth offering. Herrera huffed in a 96.2 mph fastball for his final pitch of the exchange.
Ramirez mashed the fastball over the right center field fence for a game-winning two-run homer. The Indians slugger circled the bases before being clobbered by his teammates and doused with water coolers at home plate.
The long-ball was Ramirez's first career walk-off homer. The Indians third baseman was 2-for-5 with two RBIs, a run scored and a strikeout in the win.
Chicago and Cleveland wrap up the four-game series at 1:10 p.m. Thursday in Cleveland.