Karlsson scored at 8:07 of the third period, cutting Pittsburgh's lead to 2-1. The desperate Sharks were outshooting the Penguins 8-3 in the third after the goal.
The sellout crowd of 17,562 at SAP Center came to life when Karlsson beat goalie Matt Murray from the slot, and he expected the Sharks to ride that wave of energy to at least one more goal.
Instead, the Sharks went cold again, and Penguins forward Eric Fehr scored with 2:02 remaining to seal the win.
"Of course it's tough," Karlsson said. "Still, we got one more game. We have a game again.