The area today called the Vendée was originally known as the Bas-Poitou and is part of the former province of Poitou. In the southeast corner, the village of Nieul-sur-l'Autise is believed to be the birthplace of Eleanor of Aquitaine (1122–1204). Eleanor's son, Richard I of England (the Lionheart) often had his base in Talmont. The Hundred Years' War (1337–1453) turned much of the Vendée into a battleground.

Since the Vendée held a considerable number of influential Protestants, including control by Jeanne d'Albret mother of Henry IV of France, the region was greatly affected by the French Wars of Religion which broke out in 1562 and continued until 1598. In April of that year King Henri IV issued the Edict of Nantes and the Wars came to an end. The revocation of the Edict of Nantes in 1685 caused many Huguenots to flee from the Vendée.

It is also remembered as the place where the peasants revolted against the Revolutionary government in 1793, which opened with a massacre at Machecoul in March. They resented the harsh conditions imposed on the Roman Catholic Church by the provisions of the Civil Constitution of the Clergy act (1790) and broke into open revolt after the Revolutionary government's imposition of military conscription. A guerrilla war, known as the Revolt in the Vendée, led at the outset by peasants who were chosen in each locale, cost more than 240,000 lives before it ended in 1796 (190,000 Vendeans who were republicans or royalists and 50,000 non-Vendean republican soldiers; according to the Jacques Hussenet and Centre Vendéen de Recherche Historique's book "Détruisez la Vendée"). The Revolt in the Vendée must not be confused with the revolt of the Chouans, which took place at the same time in Maine and Brittany. In 1804, Napoleon I chose La Roche-sur-Yon to be the capital of the department. At the time, most of La Roche had been eradicated in the Vendée Revolt (1793–96); the renamed Napoléonville was laid out and a fresh population of soldiers and civil servants was brought in. Napoléonville had a square-grid street network and was designed to accommodate 15,000 people.

In 1815, when Napoleon escaped exile on Elba for his Hundred Days, the Vendée refused to recognise him and stayed loyal to King Louis XVIII. General Lamarque led 10,000 men into the Vendée to pacify the region. A failed rebellion in the Vendée in 1832 in support of Marie-Caroline de Bourbon-Sicile, duchess de Berry, the former King Charles X's widowed daughter-in-law, was an unsuccessful attempt to restore the Legitimist Bourbon dynasty during the reign of the Orléanist monarch, King Louis Philippe of the French (1830–1848).

In 1850, English author Anthony Trollope published his book La Vendée, detailing the history of the region and the war. In the preface he pays tribute to Madame de la Rochejaquelein, on whose memoirs of the war he based his story.

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