The etymological origin of the word “Issy” comes from the Gaulish word “Ceton”, meaning “wood, forest”.
A 5th century necropolis offers the most ancient archaeological remains of importance in the town.
In the Middle Ages, Benedictine monks encouraged the development of vineyards, which at the time took up 76% of the land under cultivation. Winemakers became important members of society and were greatly respected. In the 17th century, Issy became a "holiday resort" for the nobility of Paris, who built country homes here, and the town played host to a great many important figures: Henri IV, Saint Vincent de Paul, Marie de Médicis, the young Louis XIII, Madame de Sévigné.

Following the Revolution in 1789, agriculture declined whereas industrial plants grew in number (the Gévelot armaments factory, the Lefranc paint company, the Grenelle laundry, the Moulineaux brewery, the tobacco factory, etc.).

In the second half of the 19th century, a wave of immigrants from the countryside, attracted by the capital’s industrialisation, submerged the town: 3,626 inhabitants in 1851, 11,111 in 1881 and 16,639 in 1901.
From 1905, the army's manoeuvre field became the “cradle of aviation”. It was here that, on 13 January 1908, Henry Farman completed the first one-kilometre loop. Today, this airfield is the heliport of Paris-Issy-les-Moulineaux. At the turn of the century, two famous artists used to visit the city: Auguste Rodin and Henri Matisse. The latter even lived and worked here from 1909 to 1917.

At the start of the 1960s, a new urban landscape gradually emerged with the departure of the companies largely responsible for generating pollution. During the 1970s the city was hit by de-industrialisation but since the election of André Santini as Mayor in 1980, the city has witnessed an unmatched economical development, doubling the number of jobs and attracting many company headquarters, in particular in the area of communications and multimedia technologies.