The Luxembourg rider, who was helped to victory by his younger brother and Leopard-Trek team-mate Andy Schleck, surged ahead when he dropped several riders up the 14km Col de L'Ospedale.
Schleck clocked a winning time of 5 hours, 20 minutes, 52 second over the 198km from Porto-Vecchio to Col de L'Ospedale.
Vasil Kiryienka of Belarus finished in second place, while Estonia's Rein Taaramae was in third. Tour de France runner-up Andy Schleck finished 10th.
Sunday's final day features a flat 75km stage in the morning, followed by a short time trial in the afternoon.
Results after first stage of Criterium international cycling race, a 198km ride from Porto-Vecchio to col de l'Ospedale in Corsica:
Stage:
1. Frank Schleck (LUX) Leopard 5hr 20min 52sec
2. Vasil Kiryienka (BLR) at 20sec
3. Rein Taaramae (EST) 28
4. David Lopez Garcia (ESP) 1min 08sec
5. Alexandre Geniez (FRA) 1:10
6. Sergey Lagutin (UZB) 1:19
7. Lars-Peter Nordhaug (NOR) same time
8. Pierre Rolland (FRA) st
9. Pierrick Fedrigo (FRA) st
10. Andy Schleck (LUX) st
Selected:
23. Andreas Kloeden (GER) 3:27, 42. Bradley Wiggins (GBR) 8:41, 89. David Millar (GBR) 27:59.
Overall:
1. Frank Schleck (LUX) Leopard 5hr 20min 52sec
2. Vasil Kiryienka (BLR) at 20sec
3. Rein Taaramae (EST) 28
4. David Lopez Garcia (ESP) 1min 08sec
5. Alexandre Geniez (FRA) 1:10
6. Sergey Lagutin (UZB) 1:19
7. Lars-Peter Nordhaug (NOR) same time
8. Pierre Rolland (FRA) st
9. Pierrick Fedrigo (FRA) st
10. Andy Schleck (LUX) st
Selected:
23. Andreas Kloden (GER) 3:27, 42. Bradley Wiggins (GBR) 8:41, 89. David Millar (GBR) 27:59.