Cruz was attempting to score from third on a chopper by Ke'Bryan Hayes when Cruz's leg bent awkwardly beneath him while attempting a late slide. Cruz's leg appeared to collide with the legs of catcher Seby Zavala, who easily tagged out Cruz.
The 6-foot-7 Cruz writhed in pain and the benches and bullpens briefly cleared after Pittsburgh designated hitter Carlos Santana appeared to take exception to Zavala's behavior.
There were no ejections and order was quickly restored.
Zavala didn't like how late Cruz decided to slide and mentioned it to Santana, leading to a brief escalation.
"I was just talking to Santana about it," Zavala said. "He didn't like what I said, he said something I didn't like. That's what happened. I think in a couple of days everybody will forget about it."
Cruz's absence will be a significant blow for a team that is off to a 6-3 start.
"It's a tough blow for sure for the team," Pittsburgh outfielder Andrew McCutchen said. "But injuries do happen and it's part of the game sometimes, unfortunately. It's got to be a 'next man up' mentality and that's what we have to have. We've got to keep going, keep pushing forward."
Cruz made his way to his feet and was helped to the bench by several members of the Pittsburgh athletic training staff. The 24-year-old had walked leading off the inning to extend his on-base streak to 19 games, the third-longest active streak in the majors.
"Obviously losing Oneil is a blow because he's a big part of what we do on both sides of the ball," Pittsburgh manager Derek Shelton said. "The flip side of that, because of the depth we've created over the last couple years we're probably in a better spot to handle it than we have been previously."
Pittsburgh continues a six-game homestand on Monday when Houston visits.