Conquered by the Romans in 311 BC, Arretium became a military station on the via Cassia, the road to expansion by republican Rome into the basin of the Po. Arretium sided with Marius in the Roman Civil War, and the victorious Sulla planted a colony of his veterans in the half-demolished city, as Arretium Fidens ("Faithful Arretium"). The old Etruscan aristocracy was not extinguished: Gaius Cilnius Maecenas, whose name is eponymous with "patron of the arts", was of the noble Aretine Etruscan stock. The city continued to flourish as Arretium Vetus ("Old Arretium"), the third largest city in Italy in the Augustan period, well-known in particular for its widely-exported pottery manufactures, the characteristic moulded and glazed Arretine ware , bucchero-ware of dark clay and red-painted vases (the so-called "coral" vases).

Around 26-261 AD the town council of Arezzo dedicated an inscription to its patron L. Petronius Taurus Volusianus. See that article for discussion of the possible political/military significance of Volusianus's association with the city.

In the 3rd to 4th century, Arezzo became an episcopal seat: it is one of the few cities whose succession of bishops are known by name without interruption to the present day, in part because they were the feudal lords of the city in the Middle Ages. The Roman city was demolished, partly through the Gothic War and the invasion of the Lombards, partly dismantled, as elsewhere throughout Europe, and the stones reused for fortifications by the Aretines. Only the amphitheater remained.

The commune of Arezzo threw off the control of its bishop in 1098 and was an independent city-state until 1384. Generally Ghibelline in tendency, it opposed Guelph Florence. In 1252 the city founded its university, the Studium. After the rout of the Battle of Campaldino (1289), which saw the death of Bishop Guglielmino Ubertini, the fortunes of Ghibelline Arezzo started to ebb, apart from a brief period under the Tarlati family, chief among them Guido Tarlati, who became bishop in 1312 and maintained good relations with the Ghibelline party. The Tarlati sought support in an alliance with Forlì and its overlords, the Ordelaffi, but failed: Arezzo yielded to Florentine domination in 1384; its individual history was subsumed by that of Florence and the Medicean Grand Duchy of Tuscany. During this period Piero della Francesca worked in the church of San Francesco di Arezzo producing the splendid frescoes, recently restored, which are Arezzo's most famous works. Afterwards the city began an economical and cultural decay, which fortunately ensured that its medieval centre was preserved.

In the 18th century the neighbouring marshes of the Val di Chiana, south of Arezzo, were drained and the region became less malarial. At the end of the century French troops led by Napoleon Bonaparte conquered Arezzo, but the city soon turned into a resistance base against the invaders with the "Viva Maria" movement, winning the city the role of provincial capital. In 1860 Arezzo became part of the Kingdom of Italy. City buildings suffered heavy damage during World War II