Chris Phillips -- playing in his 1,000th NHL game -- contributed in a big way with a pair of goals, while Milan Michalek and Bobby Butler added a pair of assists apiece for the Senators, who snapped a seven-game skid. Alex Auld made 24 saves in the victory.
Martin Erat had a goal and an assist, while Patric Hornqvist and Gabriel Bourque scored and Ryan Suter added two assists for the Predators, who have dropped three of their last four. Pekka Rinne was tagged for all four goals on 29 shots.
Ottawa struck first at 4:46 of the opening period when Spezza accepted a pass on the left wing, crossed the blue line with speed and wired a quick wrister high past Rinne.
"We were fortunate enough to get the first goal of the game," Spezza said. "It's a much easier league to play in when you're playing with the lead. We saw the product of that tonight, we got the lead and were able to hold on."
Nashville answered to tie the game at 18:46 of the first frame after Bourque buried a wrister past Auld off a nice drop pass in the slot from Jordan Tootoo.
Phillips picked up his first tally of the game at 7:50 of the second frame when he took a feed from Suter and snapped a wrister home from the slot to give the Sens the lead back at 2-1.
But, the Preds tied it at two with a power-play tally at 12:40 of the second frame when Ryan Suter let a simple wrist shot go from the left point that was deflected past Anderson by a perfectly-positioned Hornqvist in front.
The Senators though, responded with a power-play goal of their own with 1:05 to play in the second period as a result of some sloppy play by Nashville in its defensive zone.
After winning a faceoff to the left of Rinne, Nick Spaling attempted to take the puck around behind the net, but it was knocked off his stick and put home by Spezza amid a mad scramble in front.
Ottawa added a second power-play tally at 13:35 of the final stanza when Suter put a slap shot on net from the right point that was stopped by Rinne, but Phillips was there to stuff home the rebound for his second goal of the game and a 4-2 Sens lead.
Erat jammed home a rebound from in close with just 10 seconds left in regulation to pull Nashville to within 4-3, but it was too little, too late as the Sens held on for the win.
"I thought we weren't as engaged as we needed to be," Predators head coach Barry Trotz said. "We were very sloppy and if you're going to play against a desperate team, you can't play a sloppy, light game."
Nashville fell to 26-3-3 when scoring more than two goals,..Predators' forward Mike Fisher played his first game in Ottawa since being traded to Nashville last season. Fisher was taken by the Senators in the second round of the 1998 draft and played 10 full seasons with the club. He finished with a plus-1 rating in 17:36 of ice time...Nashville finished 1-for-5 on the power play, while the Senators went 2-for-6 with the man advantage.