Resen and Prespa history dates back since the Neolite. The are was settled by the ancient Macedonian tribe - Oresti. In Roman times when the famous road Via Egnatia was built, passing through the town, which at that time was a settlement called Scyrithania. Later in the 6th-7th century, the area is settled by the Slavic tribe Berizti (Brsjaci).
During the Middle Ages, the Prespa area was part of the Macedonian medieval empire - the empire lead by Samoil the nobleman. After the Battle of Kluch, some of the defeated Samoil's soldiers, who were each blinded in one eye, settled in a village on the shore of Lake Prespa. The Byzantines called the village Asamati. The Byzantine meaning of this word is "settlement of one-eyed people". From then on, Resen came under Byzantine rule.
The town is mentioned for the first time in the history as a medieval settlement in a document of tzar Dusan's codex in 1337, under the name Rosne. Later, in a document from the 16th century the settlement is mentioned under the name Resne. With the development of the merchandise and handicraft, the settlement turns into a small town.
Later, Resen became part of the Ottoman Empire, and it was the birth place of Ahmed Niyazi Bey, a Turk noble who was one of the initiators and leaders of the Young Turk Revolution which began in 1908. Bey's most famous monument in Resen is the Saraj, a chateau he built similarly to the Chateau de Chenonceau in the Loire Valley of France.
During the period of the Second World War (1941-1945), the town and the entire Prespa area experience a total tearing to pieces. Resen and the northern part of Prespa were conquered by the Buglarians, while the southern part given to the Albanian faschists (both an Axis ally).