The first traces of human presence in the area of Sirmione dates from the 6th–5th millennia BC. Settlements on palafitte existed in the 3rd and 2nd millennia BC.
Starting from the 1st century BC, the area of the Garda, including what is now Sirmione, became a favourite resort for rich families coming from Verona, then the main Roman city in north-eastern Italy. The poet Catullus praised the beauties of the city and spoke of a villa he had in the area.
In the late Roman era (4th–5th centuries AD) the city became a fortified strongpoint defending the southern shore of the lake. A settlement existed also after the Lombard conquest of northern Italy: in the late years of the Lombard kingdom, the city was capital of a judiciary district directly subordinated to the king. Ansa, wife of King Desiderius, founded a monastery and a church in the city.
Around the year 1000 Sirmione was probably a free comune, but fell in the hands of the Scaliger in the early 13th century. Mastino I della Scala was probably the founder of the castle. In the same period Sirmione was refuge for Patarines hereticals. The military role of the city continued until the 16th century, but a garrison remained in the castle until the 19th century.
Sirmione was a possession of the Venetian Republic from 1405 until 1797, when it was acquired by the Habsburg Empire. It became part of the Kingdom of Italy in 1860.