The rare sequence occurred in the sixth inning of the 4-3 setback at Guaranteed Rate Field in Chicago. The long ball was Donaldson's only hit of the game.
The Twins and White Sox were tied at 2-2 as the game entered the top of the sixth frame. Donaldson stepped into the batter's box to lead off the inning against White Sox starter Reynaldo Lopez.
The Twins infielder earned a 2-0 lead in the count before Lopez curved in an 80.3-mph slider for a strike. Donaldson was frustrated with the strike call and argued with the umpire before he returned to his stance for Lopez's fourth pitch of the exchange.
Donaldson then demolished a 2-1 inside fastball for a 381-foot blast to left field. The ball traveled 107-mph off Donaldson's bat and left the field in 4.2 seconds, according to Statcast.
Donaldson trotted around first, second and third base before he closed in on home plate. He began kicking dirt on the plate after he scored, prompting home plate umpire Dan Bellino to throw him out of the game.
"Josh's emotions got the best of him, and his frustration did get the best of him," Twins manager Rocco Baldelli told reporters.
"Does he have gripes on some of those pitches? Yeah. But that is part of baseball and something we all have to adjust to, both players and staff and everybody involved, and the umpires do, too."
Jose Abreu tied the score at 3-3 with an RBI single for the White Sox in the bottom of the next inning. Eloy Jimenez plated the go-ahead run with an RBI double in the next at-bat. The White Sox bullpen allowed just four hits in three and 2/3 scoreless innings to preserve the lead down the stretch.
Donaldson went 1 for 3 with an RBI, a run scored and a strikeout in the loss. He is now hitting .215 with five home runs and 10 RBIs this season.
The Twins (31-21) next face the Chicago Cubs at 8:15 p.m. EDT Friday in Chicago.