Mathieu -- ranked 28th in the world -- dropped the first set, but came back to beat the unseeded Seppi, 6-7 (1-7), 6-4, 7-5. Mathieu has beaten the 111th-ranked Seppi three times in three lifetime meetings between the two.
"Even if I was very tired I was fighting until the end and it's a great feeling to win this tournament," said Mathieu.
Seppi was playing in his first final.
"At the end both of us could have won and I got pretty close," said Seppi. "It is still a great week for me reaching my first final here and I've been playing very well."
Mathieu earned $80,940 for the win.