Austrian Melzer was leading 6-3 2-1 when Monfils, who has been dogged by injury throughout his career, pulled out.
Monfils has now won only four titles from 19 finals while 32-year-old Melzer is the 14th player aged over 30 to win a trophy this season.
Monfils said of the injury: "I started to feel it yesterday [Friday]. I had a sharp pain. After about 50 minutes, I tried to serve at full speed and that was it.
"I felt like something snapped a little bit and it was really painful. It was tough to continue. I will try to get an X-ray tonight [Saturday] and see what's going on."
Melzer credited new coach Galo Blanco for helping him turn his fortunes around after four straight defeats heading into the tournament.
"He started working with me in a tough moment of my career," said the Austrian. "I took four weeks off with a shoulder issue and I played terrible in Cincinnati.
"To come back a week later and win a trophy - we put a lot of work in. He talked to me a lot. It's always a team effort. My wife is here with me and she understands the game.
"Those two have done a fabulous job this week to get me going in the right direction."
Britain's Dom Inglot and his Filipino partner Treat Huey lost a close doubles final 7-6 (12/10) 7-5 to top seeds Daniel Nestor and Leander Paes.