Cruz hit three homers in his first three at-bats at Guaranteed Rate Field in Chicago. The 39-year-old finished the night 3-for-5 with five RBIs as the Twins improved to 62-40.
"It's not easy," Cruz said. "To hit three [homers] is a blessing."
At 39 years and 24 days old, Cruz is the oldest player to hit three home runs in a game since former New York Yankees third baseman Alex Rodriguez accomplished the feat four years ago, coincidentally, against the Twins.
All three of Cruz's home runs came against All-Star pitcher Lucas Giolito. He's hit seven home runs in his last seven games.
Cruz's first-inning home run traveled 473 feet, according to MLB Statcast -- his farthest in two years and the Twins' second-longest home run since 2015.
"When you see him hit balls, sometimes you think they're very unique swings, and they're very unique off the bat," Twins manager Rocco Baldelli said. "You don't see very many balls hit like that ... sometimes you can't really believe what you're watching. It's that impressive."
Cruz is hitting .278 with 25 home runs and 58 RBIs this year. He is on pace for his sixth straight season with at least 30 home runs, and is only 15 homers shy of 400 for his career.
With the win, the first-place Twins hold a two-game lead over the Cleveland Indians in the AL Central Division.