A decade of interregnum after the death of Alboin's successor (574), however, left the Lombard dukes (especially the southern ones) well settled in their new territories and quite independent of the Lombard kings at Pavia. By 575 or 576 Faroald had seized Nursia and Spoleto, establishing his duchy and sponsoring an Arian bishop. Within Spoleto, the Roman capitolium dedicated to Jupiter, Juno and Minerva had already been occupied by the bishop's cathedral (the see was founded in the 4th century) which incorporated the pagan structure (now the church of San Ansano). The Lombard dukes restored the fortifications of the high rocca, whose walls had been dismantled by Totila during the Gothic War.
The dukes of Spoleto waged intermittent war with the Byzantine Exarchate of Ravenna, and Spoleto's territories fluctuated with the fortunes of the times over much of Umbria, Lazio, the Marche and the Abruzzi. Never as important as the Duchy of Benevento, Spoleto has a fairly obscure spot in Lombard history, nevertheless. Its second Duke Ariulf made frequent expeditions against the Byzantines (579–592 against Ravenna; 592 against Rome). Ariulf was succeeded by Theudelapius, son of Faroald, whom the Catholic Encyclopedia credits with the first building of the present cathedral. Then came Atto (653), Thrasimund I (663), and Faroald II (703), who ruled conjointly with his brother Wachilap. Faroald II captured Classis, the port of Ravenna, according to Paul the Deacon's History of the Lombards: "In that time too Faroald, the first dux of the Spoletans, invading Classis with an army of Lombards, left the wealthy city despoiled and bare of all its riches." He was then obliged by the Lombard king Liutprand to restore it, a measure of the loose central control of Lombard rule that Liutprand was occupied in tightening, at least as Paul interpreted events for his Frankish patrons. At Spoleto Faroald was deposed by his son Transemund II (724), who also rebelled against Liutprand and formed an alliance with Pope Gregory III, who sheltered him in Rome in 738. Ilderic, who had replaced him as duke, was slain by Transemund in 740, but in 742 Transemund was forcibly retired to a monastery by Liutprand, who conferred the duchy that he had rewon by force of arms upon Agiprand (742). By the time of Liutprand's death (744), Spoleto was more securely in central control from Pavia, and Theodicus succeeded peaceably. Three 8th century dukes were Kings of the Lombards, a sign that in that period Spoleto was linked more closely to the kingdom than was Benevento.
In 842 the former duchy was resurrected by the Franks to be held as a Frankish border territory by a dependent margrave. Among the more outstanding of the Frankish dukes, Guido I divided the duchy between his two sons Lambert and Guido II, who received as his share the lordship of Camerino, which was made a duchy. Lambert was a doughty fighter against Saracen raiders, but who equally massacred Byzantines (as in 867), and was deposed in 871, restored in 876, and finally excommunicated by Pope John VIII. In 883 Guido II reunited the dukedom, henceforth as the Duchy of Spoleto and Camerino. After the death of Charles the Fat in 888, Guido had himself crowned Roman Emperor and King of Italy by Pope Stephen V (891). The following year Pope Formosus crowned Guido's son Lambert II as duke, king and emperor.
The dukes of Spoleto continued to intervene in the violent politics of Rome. Alberico I, Duke of Camerino (897), and afterwards of Spoleto, married the notorious Roman noblewoman Marozia, mistress of Pope Sergius III (904–911), and was killed by the Romans in 924. His son Alberico II overthrew the senatrix in 932 though her son, his half-brother, was Pope John XII. About 949 Berengar II, the Frankish King of Italy and Holy Roman Emperor, retook Spoleto from its final margrave.
At this time the Emperor Otto I detached from the Duchy of Spoleto the lands called Sabina Langobardica and presented them to the Holy See. Now the control of Spoleto became increasingly a gift of the Emperors. In 967, Otto II briefly united the Duchy of Spoleto with that of Capua and Benevento, which was then ruled by Pandolfo Testa di Ferro; but after Pandolfo's death he detached Spoleto, which in 989 he granted to Hugo, Margrave of Tuscany. The duchy was united with Tuscany a second time in 1057, when Godfrey of Lorraine espoused Beatrice, the widow of Boniface, Duke of Spoleto, and it remained so until the death of the Countess Matilda.
During the Investiture controversy with the papacy the Emperor Henry IV named other dukes of Spoleto. After this the dukedom was in the family of the Werner (Guarnieri) of Urslingen, Margraves of Ancona. The city was destroyed by Emperor Frederick Barbarossa in 1155, but was soon rebuilt. In 1158 the emperor gave the duchy to Guelf VI of Este; Henry VI invested Conrad of Urslingen with it, upon whose death in 1198 it was ceded to Pope Innocent III, but then was occupied by Otto of Brunswick in 1209, who made Dipold von Vohburg duke.
The territories of Spoleto were annexed to the Papal States and the Kingdom of Naples. The title of Duchy of Spoleto was later used by members of the House of Savoy.