Senators coach Guy Boucher confirmed his captain's return to the lineup at Monday's practice.
Karlsson missed Ottawa's first five games of the season after undergoing offseason surgery to fix tendons in his left foot.
He had 71 points in 74 games last season and added 18 points in 19 games in the Senators' run to the Eastern Conference final.
The Senators have played well in Karlsson's absence and have yet to lose in regulation this season.
Ottawa has a 3-0-2 record and is on a three-game winning streak.