In 1720, Yersinia pestis arrived at the port of Marseille from the Levant upon the merchant ship Grand-Saint-Antoine. The vessel had departed from Sidon in Lebanon, having previously called at Smyrna, Tripoli, and plague-ridden Cyprus. A Turkish passenger was the first to be infected and soon died, followed by several crew members and the ship's surgeon. The ship was refused entry to the port of Livorno.
When it arrived at Marseille, it was promptly placed under quarantine in the lazaret by the port authorities. Due largely to Marseille's monopoly on French trade with the Levant, this important port had a large stock of imported goods in warehouses. It was also expanding its trade with other areas of the Middle East and emerging markets in the New World. Powerful city merchants needed the silk and cotton cargo of the ship for the great medieval fair at Beaucaire and pressured authorities to lift the quarantine.

A few days later, the disease broke out in the city. Hospitals were quickly overwhelmed, and residents panicked, driving the sick from their homes and out of the city. Mass graves were dug but were quickly filled. Eventually the number of dead overcame city public health efforts, until thousands of corpses lay scattered and in piles around the city.

Attempts to stop the spread of plague included an Act of the Parlement of Aix that levied the death penalty for any communication between Marseille and the rest of Provence. To enforce this separation, a plague wall, or mur de la peste, was erected across the countryside. The wall was built of dry stone, 2 m high and 70 cm thick, with guard posts set back from the wall. Remains of the wall can still be seen in different parts of the Plateau de Vaucluse.

During a two-year period, 50,000 of Marseille's total population of 90,000 died. An additional 50,000 people in other areas succumbed as the plague spread north, eventually reaching Aix-en-Provence, Arles, Apt and Toulon. Estimates indicate an overall death rate of between 25%-50% for the population in the larger area, with the city of Marseille at 40%, the area of Toulon at above 50%, and the area of Aix and Arles at 25%.