The earliest evidence of man on Spetses comes in the shape of two Mesolithic flint spear-heads. These were discovered at Zogheria, and are thought to indicate a passing visit by hunters from the Fraghthi cave on the mainland who were searching for water. Spetses' first inhabitants appear to have been mostly just passing through, on their way from the Peloponnese to the Cyclades.

At the division of the Byzantine Empire, Spetses was given over to the rule of the Venetians, who were replaced by the Turks in 1460. Some time later came the Arvanite refugees from the Peloponnesus, who settled at first in the bays of Ag. Anargyri and Zogheria.

When the 1821 Revolution came, Spetses was the first of the Argo-Saronic islands to join the battle. The towns and villages of the Peloponnesus had already taken to arms, and the elders sent out a call for support to their island neighbours. The reply came back without delay, despite the fact that due to their affluence, the Spetsiots did not suffer great hardships under Turkish rule. On April 3rd the Chancellery was taken without opposition, and the ships' captains swore allegiance to the revolution. The forces of Hydra were also enlisted, after consultations between the captains of both islands.

After 1825, the Spetses merchant fleet continued to prosper for another twenty years, but then it fell into decline, taking with it the population of the island. The outlook for the island began to improve again with the return of Sotirios Anargyros from the U.S. in the early 20th century. Realising that the future for Spetses lie in tourism, he put his new-found wealth to the best possible use, constructing the road around the island, building the first hotel in the Greek islands (the Possidonion), and replacing the pine-forests of the island which had been depleted to facilitate the boat-building industry. Later he built the College which bears his name, and which for 60 years educated nobility from all over Greece.