Now the Tigers can only salvage a split of the four-game set as Max Scherzer looks to continue his home mastery of the White Sox.
Detroit will try to finish above .500 on its rain-shortened homestand Thursday when the reigning Cy Young winner goes for his fourth straight victory over Chicago at Comerica Park.
After the Tigers (10-8) had taken a two-run lead behind J.D. Martinez's two-run single and Austin Jackson's two-run homer in the fourth inning, Semien hit his first career grand slam off Ian Krol in the seventh to key Chicago's 6-4 victory Wednesday.
Jose Abreu continued his recent tear with his third home run in four games for the White Sox (11-11). The Cuban first baseman has gone 9 for 20 with seven RBIs over his last five games.
"Everybody I think is buying into catering your at-bat to the situation," said Paul Konerko, who had three hits to move past Frank Thomas atop the team's career total bases list with 3,950. "I think everybody's really done a good job of ... having an awareness of where things are at in the game, the scoreboard, what the guy's trying to do to me."
Chicago has totaled 31 runs while hitting .309 with seven homers and 14 doubles during this 3-1 stretch, but could have a difficult time extending that surge with an old nemesis on the mound.
Scherzer, who will try to lead Detroit to a 5-4 record on the homestand, has gone 5-1 with a 1.05 ERA in his last seven starts against the White Sox at Comerica Park. He's given up only six runs over 51 2-3 innings in that span, with three of them coming in the most recent matchup Sept. 20.
Former Detroit outfielder Avisail Garcia did most of the damage with a two-run homer in that contest, a 12-5 win for the Tigers. Garcia won't be around for this meeting after being ruled out for the season with a torn labrum.
Scherzer (1-1, 2.33 ERA) surrendered a leadoff home run to the Los Angeles Angels on Saturday before settling in and allowing just two more hits over seven innings in a 5-2 win that snapped Detroit's 10-game skid versus the Angels.
"For some reason, I was never concerned about the home run," manager Brad Ausmus told the team's official website. "Max looked, from that point on, like he was in control the entire game, really."
Alexei Ramirez has struggled when facing the right-hander with four hits in 42 career at-bats, while Adam Dunn is 5 for 32 with 16 strikeouts in the matchup since 2010.
Chicago's Jose Quintana (1-1, 3.75) will try to get back on track after allowing five runs and nine hits while striking out one over five frames in a 6-3 loss at Texas.
The left-hander has pitched well against the Tigers with a 2-0 record and 2.70 ERA in four career starts. He shut out Detroit on five hits over seven innings at home Sept. 11 before the bullpen gave up the only run in a 1-0 loss.
Miguel Cabrera homered off Quintana at Comerica Park in an 11-4 loss July 9, while Rajai Davis is 7 for 14 all-time in the matchup. Jackson was hitless in seven at-bats against Quintana in 2013.