Victorino leaped over the dugout railing to dispute the ejection, and manager John Farrell soon followed, halting the game for several minutes.
The outfielder's displeasure with Knight stemmed back to the call that seemed to cost Boston dearly 30 minutes earlier, when Knight rang Victorino up on a check swing that ended a bases-loaded threat.
"Obviously, Shane had a little difference of opinion on the call," said Farrell. "It was a big play in the game, leaving the bases full like that."
Victorino declined to comment on the matter following the game.
The Astros scored three runs in the bottom half of the sixth inning to take a 5-2.
Moments after Victorino's departure, the Red Sox cut into the three-run lead when Jonny Gomes drilled a two-run homer into the left-field seats.
It's not the first time an umpire has thrown Victorino out from afar. With the Phillies, he was tossed by the home-plate umpire for repeatedly raising his arms in frustration over balls and strikes calls, all while he was in center field against the Marlins on Aug. 9, 2009.
It's the 14-year veteran's fifth career ejection and first since Aug. 5, 2011, against the Giants when he was still with Philadelphia.
Victorino's exit marks the sixth ejection of the season for a Red Sox player or manager.
Chris Abshire is an associate reporter for MLB.com. This story was not subject to the approval of Major League Baseball or its clubs.