It was unclear which hit injured Karlsson. He collided with Chris Kreider early in the second period, with Kreider taking out Karlsson's legs as he fell, causing both to end up on the ice. Karlsson also got tangled up with J.T. Miller with 20 seconds remaining.
Karlsson came off the ice with six seconds left, and it was at that point he looked to be in significant discomfort.
Karlsson had been playing more than a month with two hairline fractures in his foot, sustained on a blocked shot March 28 against the Philadelphia Flyers.
He sat out five of the final seven games of the regular season but returned for the Stanley Cup Playoffs and played in all six games against the Boston Bruins in the first round, sometimes playing heavy minutes.
Karlsson played 41:51 in a double-overtime Game 5 against the Bruins, and played 37:32 in Game 2 against the Rangers, which also went to double overtime.
On Thursday, he played 14:54, leaving those additional minutes to Cody Ceci, Marc Methot and Ben Harpur. Harpur, a rookie who had played six games in the NHL prior to the start of the playoffs, has played eight games in the postseason.
"It's hard to replace Erik -- your captain -- but at the same time you've just got to try and pull by committee," forward Bobby Ryan said. "You've got five other guys. If they give a little bit more here and there and they're going to get ice time, you hope they get comfortable. That wasn't the case, but those guys filled the minutes well."
But filling the minutes is not what Karlsson does. He drives the Senators, creating constantly. He is the force behind the offense and an emotional leader who is not afraid to get in the face of his teammates, as it appeared he did with Derick Brassard in Game 2 against the Bruins.
Karlsson is the focal point of the Senators, a player who could -- and perhaps should -- have been considered a candidate for the Hart Trophy. It's hard to see the Senators advancing if he isn't able to play.
"Obviously as players you're worried," Ryan said. "That's our leader. The concern level is high. But they've got 36 hours to get him ready to go."