The win marked the Senators (3-2-2) first victory on home ice as they spent the first two weeks of the season on the road.
Karlsson opened the scoring four minutes into the game, taking a great feed from Ryan and beating Brodeur with a blast on the Senators first shot of the game.
Just over two minutes later, Turris found Ryan behind the net and Ryan scored on the wraparound.
With things looking like they could quickly spiral out of control New Jersey called a timeout.
The Devils had a number of great chances in the second, but just couldn't get anything past Anderson.
With less than two minutes remaining in the period the Senators made it 3-0 on a great passing sequence that started with Spezza finding Karlsson, who fed Smith at the side of the net. Smith fired it past Brodeur on Ottawa's fourth shot of the period.
The Senators ran into some penalty trouble at the end of the period. With Chris Phillips already in the box, Eric Gryba took a high-sticking penalty late in the period to give the Devils a 5-on-3 for 1:42.
New Jersey started the third with the two-man advantage and Zajac finally beat Anderson short side.
Anderson then robbed Jaromir Jagr with a great stick save, which made the crowd of 18, 867 chant his name.
The Devils made it 3-2 midway through the period, as the Senators were unable to clear the puck out of their own end. Bernier took advantage, jumping on a loose puck to beat Anderson five-hole.
Michalek gave the Senators breathing room as he beat Brodeur with a slapshot from just inside the blue-line with under four minutes remaining in regulation.
Spezza then made it 5-2 with an empty-net goal.
Notes: Spezza was given a huge cheer as he took to the ice at Canadian Tire Centre for the first time as team captain. ... Centre Stephane Da Costa was placed on waivers today. Defenceman Joe Corvo was a healthy scratch. … New Jersey's defenceman Mark Fayne, centre Jacob Josefson and left winger Rostislav Olesz were also healthy scratches.