Written records of the site date to the sixth century, when it was known as Restis. In 990, Eudes, the first Count of Blois, transformed it into a fortified castle. Within a decade, the Anjou realm had seized it, and Foulques Nerra gave it to Gautier I of Montsoreau, a member of one of Anjou's most prominent families. The fortified castrum quickly became one of forty strongholds in the region and one of the few granted the title of lordship at the turn of the first millennium. A town grew around the castle, and by the second half of the eleventh century, chroniclers described it as one of the most populous and well-fortified settlements in the area. The lords of Montsoreau supervised nearby Fontevraud Abbey from its founding in 1101 — Gautier de Montsoreau's own stepmother, Hersende de Champagne, served as the abbey's first abbess.

By 1450, the castle had passed through four noble families and fallen into debt. Louis II Chabot sold the domains to his brother-in-law Jean II de Chambes, one of the wealthiest men in the kingdom. Chambes had entered the service of Charles VII as a young esquire in 1426 and risen to become senior councillor, chamberlain, and eventually the king's "first master of ostel." He served as ambassador to Venice in 1459 and held governorships from La Rochelle to Aigues-Mortes. Between 1450 and 1460, while Chambes was away on diplomatic missions, his castle was rebuilt in the Flamboyant Gothic style that marks the transition from military architecture to architecture of pleasure — large windows replacing arrow slits, ornate chimneys replacing defensive towers.

The castle's later centuries brought turbulence. Protestants sacked Montsoreau in 1568, destroying the Holy Cross Collegiate Church and the town's fortifications. Four years later, Jean VI de Chambes helped organize the regional equivalent of the St. Bartholomew's Day Massacre in Saumur and Angers. By the seventeenth century, the fortress had lost its garrison. René de Chambes petitioned Cardinal Richelieu for royal troops and was refused. His fate was grimmer still: convicted of counterfeiting, he was sentenced to death and fled to England, never to return. The castle passed through increasingly indifferent owners, accumulating 400,000 livres in debts by the early eighteenth century. By 1910, its deterioration alarmed the French Archaeological Society enough that a senator intervened, and the Maine-et-Loire department began acquiring the property in 1913.

Restoration continued through the twentieth century, interrupted by two world wars. When the château reopened to visitors in 2001, it attracted about 35,000 people a year with a son-et-lumière spectacle. But the most surprising reinvention came in 2015, when French art collector Philippe Méaille signed a twenty-five-year lease and installed his collection of works by the conceptual art collective Art & Language. The result is an unlikely pairing: a fifteenth-century Flamboyant Gothic castle housing one of the world's most important collections of conceptual art. The Château de Montsoreau-Museum of Contemporary Art opened in April 2016, adding yet another chapter to a building that has been fortress, lordship, literary inspiration, and now gallery — all while keeping its foundations in the river.