Minnesota got to Chicago early with help from Lewis in the second inning. The Twins loaded the bases with two outs before the rookie followed with a home run to left field for a 4-0 lead.
Lewis, who entered Friday hitting .323 over his last 45 games, has five grand slams in 66 career games (4 this season, 1 last season), passing Alexei Ramírez for the most grand slams by a rookie in MLB history.
"I'm absolutely amazed," Minnesota manager Rocco Baldelli said. "I've never seen anyone do anything like this in my life on any level ... high school, college or anything. I've never seen anyone do that."
Lewis deflected the spotlight when asked about his new place in Twins history.
"I think about the wins that come with [setting the record]," Lewis said. "It seems like every time I hit one we've won the game, so hopefully we can keep doing that and have some other guys hit some too, which would be great."
All four of Lewis' grand slams this season have come in his last 18 games, the shortest span to hit four grand slams in MLB history (Don Mattingly is next, accomplishing the feat in 39 games during the 1987 season, and Travis Hafner in 44 games in 2006).
The Twins have won sixth straight against the White Sox, their longest win streak against Chicago within a season since 2011.
ESPN Stats & Information and The Associated Press contributed to this report.