The island of Spetses was first occupied during the Mesolithic Age, in around 8000 BC. During that period the island was connected by an isthmus to the mainland of Argolida, at the point now named Kosta. 

In the 15th century, the Venetians who ruled the island since 1220, named it Spezia (“Spice”) for its position on a major trade route that dealt in spices. Over time the name was Hellenised to Spetsai (Spetse/Spetses).

The Greek Coalition, in cooperation with the Russians in the Russian-Turkish war in 1768–1774, turned the powerful merchant fleet of Spetses to a significant power against the Ottoman Empire during the so-called Orlov Revolt. In response to these events, in 1770 the Turks destroyed the only village on the island.

For some years after the destruction of the village, the island was deserted. It was re-occupied in 1774 by new settlers from the opposite coast of Peloponnese after the Treaty of Küçük Kaynarca. 

From 1821, the island played an important role in the Greek War of Independence, and it was the home of celebrated war heroine Laskarina Bouboulina. Her life sized statue can be seen in the main dock. Spetses was the first of the Greek islands to raise the flag of Revolution the morning of 3 April (O.S.) 1821. 

Its fleet, consisting of merchant ships, played a key role in the involvement of the Spetsiote fleet in sieges of the fortresses of Nafplion and Monemvasia and naval battles of Samos (1824) and Kafireas (1825). 

Along with their counterparts in nearby Hydra, Spetsiote captains were so wealthy they had been hoarding their gold in wells, a wealth that they tapped to fund the war of liberation.

Sotirios Anargyros a descendant of a great 18th-century Spetsiot shipping family, emigrated to the United States as a young man in 1868, when Spetses was declining as a maritime centre. In 1899 he returned from the US, now a wealthy tobacco tycoon and started to transform the island by planting the pine forest, building The Poseidonion Hotel and attracting wealthy visitors.