Perugia was an Umbrian settlement but first appears in written history as Perusia, one of the 12 confederate cities of Etruria; it was first mentioned in Q. Fabius Pictor's account, utilized by Livy, of the expedition carried out against the Etruscan League by Fabius Maximus Rullianus in 310 or 309 BC. At that time a thirty-year indutiae (truce) was agreed upon; however, in 295 Perusia took part in the Third Samnite War and was reduced, with Volsinii and Arretium (Arezzo), to seek for peace in the following year.
In 216 and 205 BC it assisted Rome in the Second Punic War but afterwards it is not mentioned until 41–40 BC, when Lucius Antonius took refuge there, and was reduced by Octavian after a long siege, and its senators sent to their death. A number of lead bullets used by slingers have been found in and around the city. The city was burnt, we are told, with the exception of the temples of Vulcan and Juno— the massive Etruscan terrace-walls, naturally, can hardly have suffered at all— and the town, with the territory for a mile round, was allowed to be occupied by whoever chose. It must have been rebuilt almost at once, for several bases for statues exist, inscribed Augusto sacr(um) Perusia restituta; but it did not become a colonia, until 251–253 AD, when it was resettled as Colonia Vibia Augusta Perusia, under the emperor C. Vibius Trebonianus Gallus.
It is hardly mentioned except by the geographers until it was the only city in Umbria to resist Totila, who captured it and laid the city waste in 547, after a long siege, apparently after the city's Byzantine garrison evacuated. Negotiations with the besieging forces fell to the city's bishop, Herculanus, as representative of the townspeople. Totila is said to have ordered the bishop to be flayed and beheaded. St. Herculanus (Sant'Ercolano) later became the city's patron saint.
In the Lombard period Perugia is spoken of as one of the principal cities of Tuscia. In the 9th century, with the consent of Charlemagne and Louis the Pious, it passed under the popes; but by the 11th century its commune was asserting itself, and for many centuries the city continued to maintain an independent life, warring against many of the neighbouring lands and cities— Foligno, Assisi, Spoleto, Todi, Siena, Arezzo etc. In 1186 Henry VI, rex romanorum and future emperor, granted diplomatic recognition to the consular government of the city; afterward Pope Innocent III, whose major aim was to give state dignity to the dominions having been constituting the patrimony of St. Peter, acknowledged the validity of the imperial statement and recognised the established civic practices as having the force of law.
On various occasions the popes found asylum from the tumults of Rome within its walls, and it was the meeting-place of five conclaves (Perugia Papacy), including those that elected Honorius III (1216), Clement IV (1265), Celestine V (1294), and Clement V (1305); the papal presence was characterised by a pacificatory rule between the internal rivalries. But Perugia had no mind simply to subserve the papal interests and never accepted papal sovereignty: the city used to exercise a jurisdiction over the members of the clergy, moreover in 1282 Perugia was excommunicated due to a new military offensive against the Ghibellines regardless of a papal prohibition. On the other hand, side by side with the 13th century bronze griffin of Perugia above the door of the Palazzo dei Priori stands, as a Guelphic emblem, the lion, and Perugia remained loyal for the most part to the Guelph party in the struggles of Guelphs and Ghibellines. However this dominant tendency was rather an anti-Germanic and Italian political strategy. The Angevin presence in Italy appeared to offer a counterpoise to papal powers: in 1319 Perugia declared the Angevin Saint Louis of Toulouse "Protector of the city's sovereignty and of the Palazzo of its Priors" and set his figure among the other patron saints above the rich doorway of the Palazzo dei Priori. Midway through the 14th century Bartholus of Sassoferrato, who was a renowned jurist, asserted that Perugia was dependent upon neither imperial nor papal support. In 1347, at the time of Rienzi's unfortunate enterprise in reviving the Roman republic, Perugia sent ten ambassadors to pay him honour; and, when papal legates sought to coerce it by foreign soldiers, or to exact contributions, they met with vigorous resistance, which broke into open warfare with Pope Urban V in 1369; in 1370 the noble party reached an agreement signing the treaty of Bologna and Perugia was forced to accept a papal legate; however the vicar-general of the Papal States, Gérard du Puy, Abbot of Marmoutier and nephew of Gregory IX, was expelled by a popular uprising in 1375, and his fortification of Porta Sole was razed to the ground.
Civic peace was constantly disturbed in the 14th century by struggles between the party representing the people (Raspanti) and the nobles (Beccherini). After the assassination in 1398 of Biordo Michelotti, who had made himself lord of Perugia, the city became a pawn in the Italian Wars, passing to Gian Galeazzo Visconti (1400), to Pope Boniface IX (1403), and to Ladislaus of Naples (1408–14) before it settled into a period of sound governance under the Signoria of the condottiero Braccio da Montone (1416–24), who reached a concordance with the Papacy. Following mutual atrocities of the Oddi and the Baglioni families, power was at last concentrated in the Baglioni, who, though they had no legal position, defied all other authority, though their bloody internal squabbles culminated in a massacre, 14 July 1500. Gian Paolo Baglioni was lured to Rome in 1520 and beheaded by Leo X; and in 1540 Rodolfo, who had slain a papal legate, was defeated by Pier Luigi Farnese, and the city, captured and plundered by his soldiery, was deprived of its privileges. A citadel known as the Rocca Paolina, after the name of Pope Paul III, was built, to designs of Antonio da Sangallo the Younger "ad coercendam Perusinorum audaciam."
In 1797, the city was conquered by French troops. On 4 February 1798, the Tiberina Republic was formed, with Perugia as capital, and the French tricolour as flag. In 1799, the Tiberina Republic merged to the Roman Republic.
In 1832, 1838 and 1854, Perugia was hit by earthquakes. Following the collapse of the Roman republic of 1848–49, when the Rocca was in part demolished, it was seized in May 1849 by the Austrians. In June 1859 the inhabitants rebelled against the temporal authority of the Pope and established a provisional government, but the insurrection was quashed bloodily by Pius IX's troops. In September 1860 the city was united finally, along with the rest of Umbria, as part of the Kingdom of Italy. During World War II the city suffered only some damage and was liberated by the British 8th army on 20 June 1944.