The win allowed the Predators (27-28-10) to snap a four-game losing streak.
Craig Anderson allowed three goals on 29 shots before leaving the game early in the third. Lehner faced 13 shots in relief.
Holding a 3-0 lead the Predators nearly let the game slip away in the third as the Senators scored twice in a span of 2:39.
Spezza then tied the game with 67 seconds remaining in regulation. The newly acquired Ales Hemsky, who had three assists, found Spezza at the side of the net and the Senators captain banged it in.
The comeback started midway through the third, as Cowen was able to find the puck through traffic in front and push it past Rinne.
Spezza picked up his second assist of the night as he found a surging Methot to make it a 3-2 game at the halfway mark.
The Predators three unanswered second period goals appeared to make this game look all but decided.
Anderson could hardly be blamed for any of the goals as he was the victim of two redirections and a giveaway. Anderson's night came to an end at 4:10 of the third after he was hit in the head by teammate Milan Michalek.
On the first goal Spaling tipped a Michael Del Zotto point shot at the eight-minute mark of the second.
Less than two minutes later Colin Wilson won the faceoff in the Senators end and got the puck to Jones on the point. The blue liner then passed it to Mattias Ekholm, who took a shot that Smith re-directed in front.
The Predators made it 3-0 on Nystrom's unassisted goal. Methot went to clear the puck and it landed directly on Nystrom's stick for the easy finish on Anderson.
A scoreless first period was highlighted by the damage inflicted by Shea Weber's powerful shot.
First, Anderson dropped to the ice after taking a Weber shot in the shoulder and minutes later Cody Ceci took a shot to the head that left him with a lacerated right ear. He did not return to the game.
Notes: The Senators were without LW Clarke MacArthur as he has a hand injury, but is expected to return for Saturday's game against Montreal. D Patrick Wiercioch, was a healthy scratch for the Senators… LW Gabriel Bourque and D Victor Bartley were healthy scratches for the Predators….The CIS Men's Basketball Champion Carleton Ravens were honoured before the game and took part in the ceremonial puck drop.