Founded by Gauls in the 1st century BC, the ancient town on the site of Saint-Malo was known as the Roman Reginca or Aletum. By the late 4th century AD, the Saint-Servan district was the site of a major Saxon Shore promontory fort that protected the Rance estuary from seaborne raiders from beyond the frontiers. According to the Notitia Dignitatum, the fort was garrisoned by the militum Martensium under a dux (commander) of the Tractus Armoricanus and Nervicanus section of the litus Saxonicum. During the decline of the Western Roman Empire, Armorica (modern-day Brittany) rebelled from Roman rule under the Bagaudae and in the 5th and 6th centuries received many Celtic Britons fleeing instability across the Channel. The modern Saint-Malo traces its origins to a monastic settlement founded by Saint Aaron and Saint Brendan early in the sixth century. Its name is derived from a man said to have been a follower of Brendan the Navigator, Saint Malo or Maclou, an immigrant from what is now Wales.

Saint-Malo is the setting of Marie de France's poem "Laüstic," a 12th-century love story. The city had a tradition of asserting its autonomy in dealings with the French authorities and even with the local Breton authorities. From 1590 to 1593, Saint-Malo declared itself to be an independent republic, taking the motto "not French, not Breton, but Malouin."[10]

Saint-Malo became notorious as the home of the corsairs, French privateers and sometimes pirates. In the 19th century, this "piratical" notoriety was portrayed in Jean Richepin's play Le flibustier and in César Cui's eponymous opera. The corsairs of Saint-Malo not only forced English ships passing up the Channel to pay tribute but also brought wealth from further afield. Jacques Cartier lived in, and sailed from, Saint-Malo to the Saint Lawrence River, visiting the villages of Stadacona and Hochelaga that would later become the sites of present-day Quebec City and Montreal respectively. As the first European to encounter these sites and learning the local word "Kanata" (meaning a group of houses), Cartier is credited as the discoverer of Canada.