It was founded in approximately 1000 AD, during the Saracen Arab era of Sicily, being named initially as "Manzil Jusuf" (as known in Arabic) in honor of Yusuf-Abd-Ibd-Allah, the last reigning Emir of Palermo, who was deposed in 1072 by Norman conquerors.

The Normans, after 60 years, granted "Mensiliusuph" (as known in Norman-French) as a ecclesial fief, in 1132, to the Monastery of Saint John of the Hermits, in Palermo. This Monastery ruled the village for nearly 400 years, throughout the times of the Norman-French, Swabian-German, Anjevin-French, Aragonese and early Spanish periods of Sicily.

The Monastery's abbots governed this village of "Mezojuso" (as known in common Latin) or "Medii usum" (as known in high Latin) during its gradual decline in the 1400's when it became nearly depopulated. The abbots then permitted, by charter in 1501, that 48 Albanian (Arbėresh) soldiers and their families could officially settle in this village, also called "Munxifsi" (as known in Arbėresh).

The abbots subsequently granted the village as a baronial fief, in 1527, to the noble lord Giovanni Corvino (with ancestry from Pisa), a high-ranking and prominent administrator in Palermo. The Corvino family ruled for just over 300 years, until 1832, when the village's feudal status ended upon the death of Francesco Paolo Corvino Filingeri, who left no heirs.

In 1832, local appointed politicians began to govern "Mezzojuso" (spelled with a "j" due to Spanish influence), also called "Mezzoiuso" (spelled with an "i" due to Italic influence), during the harsh Bourbon-Spanish era. In 1856, numerous Mezzojusari assisted the rebellious Francesco Bentivenga in an uprising in Palermo, but they were subsequently captured and executed by the Bourbons.

In 1860, the revolutionary general Giuseppe Garibaldi and his Thousand Red-Shirts landed by ship at Marsala, in order to liberate Sicily and mainland Italy, and 150 Mezzojusari joined Garibaldi in this campaign. Later, during 2-4 August 1862, Garibaldi actually stayed in Mezzojuso, tumultuously greeted by the Mezzojusari.

Since 1860, elected officials have managed Mezzojuso / Mezzoiuso. The village's inhabitants still proudly celebrate their distinguished history, and their unique dual Catholic heritage as practiced in the Roman rite as well as in the Byzantine (Italo-Albanian) rite.