The authors agree that this surname derives from the place name Mandello del Lario, a locality situated in the Lecco area, in the region of Lombardy. E. Rossoni notes that the surname appears to originate in the Como area and that its greatest concentration is recorded in the provinces of Bergamo, Milan and Como.

The Mandelli are held to have been a noble Milanese family with a documented presence from the communal period, in which they figured as consuls and as podestà. Some of its members were taken prisoner by Frederick II at the battle of Cortenuova (1237) and transferred to the kingdom of Naples. The family appears included in the Matricola Nobilium Familiarum of Milan of 1377, a register which granted its members the right to be elected canons of the Duomo of that city.