Karlsson finished with a goal and two assists to set a new franchise record for assists by a defenseman in a season with 47.
The 21-year-old now has seven points in his last two games. His 60 points on the season give him a 20-point lead on Florida's Brian Campbell for the NHL lead in scoring by a defenseman.
Michalek added two goals and an assist, while Chris Phillips, with his fourth goal in six games, also scored for Ottawa. Craig Anderson made 33 saves.