The town of Desenzano del Garda stands, fanned out, on the first ring of the Morainic amphitheatre, today it is one of the most important residential, commercial and tourist areas on the lake. The name of this village on Benaco was derived from Decentianum, which was the term used to describe the farm, country estate and country residence of the wealthy Roman Decentius. Finds dating back to the Old Bronze Age (2000 - 1800 B.C.) place human settlements, characteristic of the "Polada Culture", in the Morainic amphitheatre of the Benaco, proof was discovered by professor Giovanni Rambotti in 1873 in the peat-bog situated between Desenzano and Lonato.

During the Longobard era Desenzano was part of a district which stretched from the lower shores of the lake to the Mantuan countryside. The parish church of Desenzano, one of the first Christian churches on Lake Garda, was at first dependent on Verona, then it came under the civil jurisdiction of Brescia in 1192, later, in 1220 it became part of the Confalonieri family's estates. Around 1170 Niceta brought the Catharist heresy to these parts: Sirmione and Desenzano, which also had a Catharist theologian and bishop, became the central points of diffusion until the interventian of the Inquisition in 1276. During the dispute between the Guelphs and Ghibellines the latter found refuge in the castle at Desenzano but in the end they were defeated.

From 1426, with the Venetian rule, Desenzano entered the "Magnifica Patria" becoming an important commercial centre thanks, above all, to its corn market, as well as an important cultural centre; by 1449 public teaching was already being held in Desenzano and in the 1500s an Academy was built. During the French League of Cambrai invasion Desenzano refused to give itself up to Cardinal d'Amboise and placed itself under the protection of Mantua, but it was, however, forced to bow to Louis XII. From 1512 to 1516 there was plundering by German troops. The 1500s held other misfortunes such as the passage of the lansquenets and the plague of 1567.

In 1772 , after almost 350 years of conflict, Desenzano managed to obtain independence from Salò. After the Jacobinic Revolution of 1797 it became the seat of the District of Benaco. With the Restoration, under the Lombard-Veneto reign Desenzano was elevated to first class municipality status and in 1816 and 1821 it received visits from the Austrian Emperor Francis I. In 1859 the battle of San Martino and Solferino (Napoleon III and Victor Emanuel II against the Austro-Hungarians) saw the birth of The Red Cross, thanks to Henri Dunant. The Red Cross museum, the only one in the world, is situated just a few kilometres from Desenzano in the town of Castiglione delle Stiviere. This event transformed Desenzano into one big hospital. Both during the first and second World Wars Desenzano was subjected to bombardments which in the final conflict destroyed the railway viaduct in 1945.