Vokoun made 14 saves in the first period as the Penguins -- who have clinched the Eastern Conference's first seed -- were getting goals from Dustin Jeffrey and Jarome Iginla for a 2-0 lead.
The victory was the 300th of the veteran netminder's 15-year career.
Tyler Kennedy also found the net for Pittsburgh.
Patrick Wiercioch scored and Craig Anderson yielded three goals on 24 shots for the Senators, who are still battling for an East playoff spot with 52 points.
With Winnipeg's win against Buffalo earlier Monday, Ottawa's lead over the ninth-place Jets dwindled to a single point.