Pittsburgh (8-5-0) had its five-game winning streak halted with a 3-1 loss at New Jersey on Saturday, and then lost by the same score the following day to get swept in the home-and-home set.
The Penguins, though, were without Letang (lower-body) and Niskanen (ankle), who have missed three and eight games, respectively.
Both returned to practice this week and could be back against Ottawa (7-4-2)
"I'm not going to put them there right now, but yes, it could be that (they are game-time decisions)," coach Dan Bylsma told the team's official website.
Letang's potential return may be more influential since he has three goals and six assists in 10 games with a plus-4 rating after posting a career-high plus-21 in 2011-12. He's totaled 92 points over the last two seasons, while his 74 assists rank fourth in the league among defensemen in that span.
Despite that success, he has just three points and is a minus-3 in 18 career meetings with the Senators.
"Felt pretty good," Letang said of returning to practice. "It was the first time I've practiced with the team so I had a chance to battle in the corner. I stayed later to do extra. It felt pretty good.
"It was easy to tell when I'm hurt or feeling better. (Tuesday) I felt really good on the ice. Two days ago it didn't feel really well."
Getting back on the scoresheet would surely make Sidney Crosby feel better. The superstar center is among the league's scoring leaders with 17 points, but he failed to get one over the weekend versus the Devils, snapping his six-game streak -- during which he had two goals and 10 assists.
He failed to get a point before finding the net in the shootout to clinch a 2-1 win at Ottawa on Jan. 27.
Still, Crosby has been a dominant presence in the series, getting 49 points in 38 meetings -- including the playoffs -- while totaling 28 in 18 home matchups.
Those number may increase since Crosby wants to spend more time in the offensive zone.
"We need to play more in the opponent's zone," he said. "Our offensive zone time needs to get better. That's something we pride ourselves on. We want to improve in that area."
Getting there may not matter if Craig Anderson is back in net and able to build on his best performance of the season. He had a season-high 42 saves in Tuesday's 2-0 win over Buffalo after surrendering three goals in each of his previous two starts.
Anderson is 7-2-2 with a 1.36 goals-against average, but one of those defeats came against Pittsburgh on Jan. 27. He made 33 saves through overtime before giving up goals on all three shootout attempts. However, he's 4-2-1 with a tie and a 2.20 GAA in nine career meetings against them.
Erik Karlsson has three goals in four games after getting his first short-handed tally against the Sabres.
"I think when you're one man short you can even create some momentum there," Karlsson said. "It's going to be good for the team if you see an opportunity once in a while."
The reigning Norris Trophy winner's six goals lead all blueliners, and he has 16 points in 17 career meetings with Pittsburgh.