The Blue Jackets (0-7-1) are the league's only winless team. The have a league-low one standings point on the season.
"I feel for these guys," Blue Jackets coach Scott Arniel said. "These guys busted their tail after playing (Friday) night. We came in here and worked our tails off. I'm so disappointed for these guys."
The Blue Jackets scored more than two goals for the first time this season.
"We played well for 59 minutes and then they got to us at the end," said Nash, who was playing in his 600th game.
"It's tough. It seems like we're not getting any bounces. It seems like we're finding ways to lose games instead of finding ways to win games. That's the difference between good teams and bad teams right now."
The Senators opened the scoring with a power-play goal as Spezza found Kuba all alone, and the defenseman beat Mason through his legs.
The Blue Jackets tied the game midway through the period as Johnson dived on a rebound left in the crease.
The Senators came out flat to start the second as they got caught on the wrong end of a 4-on-2 break, and Russell beat Anderson just 16 seconds into the period.
After missing on a couple of early opportunities, Smith scored his first of the season with a quick snap shot off a feed from Erik Condra from behind the net.
The Blue Jackets took the lead with a power-play goal by Nash, who beat Anderson from just inside the blue line.
Holding a 3-2 lead with less than one minute remaining Nash said the team felt pretty good about its chances for the win.
"It seemed too good to be true for our season right now," Nash said. "We're in tough times. We've got to stay up, we've got to stay positive and leaders have to lead and keep making the young guys follow, but (Saturday) I'm speechless for what happened."
Ottawa's Daniel Alfredsson had a great chance to tie it up late in the period, but was stopped by Mason and dragged down by Russell. Spezza tied the game on the ensuing power play.
Alfredsson has been a focal point for Ottawa's offense the past two games. He forced turnovers, was strong on the forecheck and created havoc against the Blue Jackets.
"It's fun to play when I'm able to do those things," Alfredsson said. "That's what I enjoy the most."