The archaeological finds allow us to think that already in prehistorical times, Iseo was an important centre of exchange between different populations like Reti, Camuni and Cenomani, especially thanks to its lacustrine port. The Camuni in particular needed the port to import provisions like wheat, which was possible only via the plain and the lake as there was no coast road at the time. Moreover, Iseo was located along the ancient transhumance road that led to Mount Guglielmo; this allowed its inhabitants the right to impose tolls on the transit of cattle that stopped in the great Pianura Padana ,south of the town.

The Roman influence in the area is testified by efficient means of communication like the Via Valeriana (first century B.C.), and by an artefact that represents the Labours of Hercules, discovered during excavations in the parish church of Saint Andrea (sixth century), once an ancient Roman temple. This church was built thanks to the bishop of Brescia Saint Vigilio when Christianity was diffused in the Longobard Age. The parish of Saint Andrea included Polaveno, Brione, Ome, Monticelli, Provezze, Provaglio, Timoline, Colombaro, Clusane, Pilzone, Saint Paolo island and was later enlarged by numerous donations of ground that however were taken away again by Seignories and Free Cities. The Longobard monastery of Saint Giulia was also located in this area.

During the Middle Ages, after the Barbarian invasions, a number of fortifications and castles were built in the area of Franciacorta and Sebino.
Iseo, with its castle owned by the Oldofredi family, had become such an important strategic and commercial point for Brescia that it was sacked and set to fire during the war between Italians and the emperor Federico I Barbarossa ( X-XII century). The municipality of Brescia financed the rebuilding of the castle and granted its citizens special privileges.
In 1427 Iseo joined the Serenissima Venetian Republic and during the following three centuries it underwent great social and economical changes only interrupted by the spread of the Black Death in the seventeenth century.
Economic recovery was later guaranteed by the development of the wool and silk industry; in 1784 the wool craftsmen formed an association known as “università”, which proves the importance of the trade.
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In the nineteenth century the Asburgo brought public illumination, a new cemetery(1822) and a new hospital (1841). In 1834 regular navigation lines on the lake were introduced.
Twelve inhabitants of Iseo fought on the barricades during the “Dieci Giornate di Brescia”, where the 40-year-old Camillo Plevani lost his life and tenant Giuseppe Nulli was wounded. When the Austrians left the village, the Italian tricolour was immediately raised in the port and Giuseppe Zanardelli, the envoy of the new Government, found a cheering population on his arrival. A few years later the people from Iseo saluted enthusiastically the troops of Giuseppe Garibaldi.
An eminent citizen of Iseo was Gabriele Rosa, scholar and leader of the local republican group, who played an important role in Giuseppe Zanardelli’s political success.
In 1870/80 three steam spinning mills were opened and in 1865 the port was enlarged. Ten years later Brescia and Iseo were connected by a railway line which was extended up to Edolo in 1907, thus causing Iseo to lose its important role as a commercial knot to Val Camonica. Still remembered for the damage caused to the whole area is the flood of September 1888.

In the 20th century, during the First World War, the pilots of seaplanes trained on the lake. In the Thirties tourists started coming to Iseo to enjoy its lakeside walk completed in 1937.