After a 133.4km ride in Haute-Garonne near the Spanish border, the 22-year-old Movistar starlet finished in the third group of riders, 12 seconds behind Italian stage winner Manuel Belletti.
That was more than enough to hold off nearest challenger Hubert Dupont, with Quintana – who surged into the lead with a fantastic stage three win on Saturday – finishing 48 seconds ahead of the Frenchman.
Another Frenchman, Europcar’s Anthony Charteau, finished third overall, nearly four minutes off Quintana.
On the day France’s Stephane Poulhies and Spain’s Juan Jose Lobato finished second and third respectively as a 17-rider bunch sprint was shaded by AG2R’s Belletti.
Quintana - who won the Vuelta a Murcia in south eastern Spain in March - has not been selected for this summer’s Tour de France, but he is expected to feature prominently in Movistar’s Vuelta a Espana campaign.
He also won the penultimate stage of the Criterium du Dauphine earlier this month.