The Romans manifested themselves in the second century B.C.
In 125 B.C., Marseille, at war with the Salyens, calls on their allies the Romans. They do more than deliver the people of Marseille; they completely destroy the oppidum of Entremont, the Salyen capital. (south of which they founded the city of Aix, the province capital.) In 121 B.C., the Cavares of Aquenion surrender practically without resistance and the oppidum becomes gallo-roman, taking the name of Avenio.
The Romans settled in the region and established the transalpine province "Narbonnaise", which extends from the Alps to the Pyrenees, and of which Narbonne is the capital.
During the conflicts between Pompeii and Caesar, Marseille sides with Pompeii. Caesar, conqueror, puts down the city and punishes her by suppressing her regional prominence. In 49 B.C., Avignon, like Orange, Apt and Carpentras becomes a latin city.

If Avignon today does not have the same prestige as Arles, Nimes and Orange for their gallo-roman past, it is because very few monuments from this period remain. For as much as that, hidden traces regorge - the Forum, the city's center, was located at the present day Place de l'Horloge. At the time of its expansion, the agglomeration extended over 46 hectares and counted a population of approximately 25,000. The city was fortified, and like all Roman cities, endowed with temples, senate buildings and triumphal arches. Even if Avignon did not have the influence of Arles or Nimes, it was an important religious, administrative and commercial center. The proximity of the Via Agrippa, one of the largest Roman routes, assured Avignon a certain renown. The invasions and destruction which followed left few visible traces of this glorious presence, although we continue to discover a multitude of evidence during digs and construction work.

Situated in the passage between North and Southern Europe, the region of Avignon was well whipped by the barbarian invasions.

The first wave hit at the end of the 3rd century, with the onslaught of the Franks and Alemans. It left the south with a lasting and terrible souvenir. The second, submerging wave, in the beginning of the 5th century, cut off completely the already deteriorating Roman Empire from the West.
The vandals devastated the country, followed by the Goths, then the Burgundes, who established themselves in the region. In 474 A.D., Avignon became a part of their realm, of which she was the southernmost fortification.

In these troubled times, decimated by the wars and pillaging, the inhabitants fled the villages. Avignon, like Nimes, was reduced to a seventh of its former size. What remains of the Roman city was fortified by a rapidly constructed shorter and more easily defended wall encircling the cliff where the population had taken refuge.

In the year 500, the Burgundian king, Gondebaud, pursued by the Frankish king Clovis, took refuge in Avignon. The latter did not succeed in taking the heavily fortified city. The city came under Visigoth control towards 506 A.D., followed by the Ostrogoths two years later. In 537, King Vitiges ceded Avignon and Provence to the Frankish king. The city was incorporated into the Frankish kingdom of Burgundy in 561 until the second half of the 8th century.