The city, once known as Urbinum Mataurense, was a stronghold during the Gothic Wars in the 6th century. In 538 it was conquered by the Ostrogoths through the Byzantine general Belisarius.

Pepin the Short gave Urbino to the papacy in 754.The town was later somewhat independent until about 1200 when it became the property of the House of Montefeltro. They obtained the office of Podesta in 1213, but the population rebelled and allied with the municipality of Rimini (1228), which finally regained its independence in 1234. However, the nobles of Montefeltro eventually took control again and kept it until 1508. In the battles between the Guelfs and the Ghibellines, when the factions supported either the papacy or the Holy Roman Empire, the Montefeltro lords of Urbino were the leaders of the Ghibellines in Marche in the 13th and 14th centuries.

This almost completely preserved Renaissance city acquired essential parts of its current appearance in the 15th century, under the rule of Duke Federico da Montefeltro, who wanted to build an "ideal city" with Urbino.

The first cathedral on this site was built around 1021, replacing another that stood outside the city walls. Under the patronage of Count Federico da Montefeltro, reconstruction took place in the 15th century to a design by Francesco di Giorgio Martini. After damage from the 1781 earthquake, the dome collapsed in 1789 after another strong earthquake and had to be rebuilt. This project was completed in 1801. The reconstruction was carried out in the neoclassical style.