Medina Garrigues posted a 6-4, 4-6, 6-4, victory for her second title in Strasbourg. She also won this tournament in 2005 and now has seven career WTA singles crowns.
Mauresmo, the top seed, played her second straight three-set match. She had to struggle past fellow Frenchwoman Marion Bartoli in Friday's semifinals.
Medina Garrigues didn't play Friday thanks to a walkover win against an ill Jelena Jankovic. The extra rest appeared to help Medina Garrigues, who had never beaten Mauresmo in four previous matches.
Mauresmo was seeking her second title of 2007 and the 25th of her career. She won in Antwerp in February but lost a title match later that month in Dubai to Justine Henin.