While the Bronze and Iron Ages witnessed the penetration of external influences into Midi-Pyrénées, it is the Roman conquest in 200 BC that was decisive, initiating a long period of prosperity. Between the 3rd and the 5th century, successive invasions of the Alemanni, the Vandals and the Visigoths swept the region and Toulouse became capital of the Visigoth Kingdom. In 801, Charlemagne marched into Spain and absorbed Catalonia into his Empire, although he allowed it a degree of autonomy. After his death, the Counts of Toulouse took control of seven cities and of the Rouergue district, asserting their power by launching great construction programs. In the 1200s, the Cathar heresy was quelled by fierce crusades, the University of Toulouse was created, and Perpignan became capital of the Kingdom of Majorca and the Balearic Islands. A century later, the Quercy and Rouergue districts were ceded to the King of England (although many years later the 1659 Treaty of Pyrénées restored them to the French crown). In 1271 Toulouse came under French rule.

In 1484, the Kings of Navarre gained control of the Pays de Foix and Bigorre territories and held them until 1512, when King Ferdinand of Spain reclaimed them. Both territories were returned to France in the 17th century.

The Napoléonic era witnessed the discovery of the Pyrénées’ first thermal springs, which were transformed into full-fledged spa resorts under the Second Empire and the Third Republic. During World War II, the Pyrénées proved to be of vital importance to the French Resistance movement.