He was replaced on an interim basis by associate coach Rick Tocchet.
Melrose, longtime NHL analyst for the ESPN cable sports network, was hired on June 24 after the Lightning changed ownership, but the team's record is 5-7-4 through 16 games.
"This was a tough decision to make," said Lightning general manager Brian Lawton. "Barry is a good man and we have a great deal of respect for him. We wish him nothing but success. However, the results were unacceptable and the players have to understand that we need to be better. Hopefully this change helps push them."
Melrose went 79-101-29 in two full seasons and part of a third with the LA Kings.
He is the second coach fired since the start of the season following Chicago's Denis Savard on Oct. 16 after a 1-2-1 start.