In this territory there is evidence of settlements and remains of Sicanians, Greeks and Romans, and the town had once been a mountaintop stronghold of Berbers and later of Arab civilization.

Afterwards with the arrival of the Normans, the territory of Casale Manzil-Sindi was named "Misilindino" or "Misirindino", then it became part of the feudal estate of a Spanish nobleman, Baron Antonio de Corbera, responsible for the first built-up area in 1572.

The princes Filangeri, who succeeded the barons Corbera, gave impetus to the village by construction of several buildings and increasing the population.

In 1812 for about three months, Nicolo I hosted King Ferdinando, Queen Maria Carolina (the Donnafugata) and Prince Leopoldo di Borbone in the Palazzo of Santa Margherita.

Many of the damaged structures from the earthquake are still standing, including the ruined palace of Giuseppe Tomasi di Lampedusa and the Palazzo Filangeri-Cutò.