A first cathedral of Arezzo was built on the nearby Pionta Hill, over the burial place of Donatus of Arezzo, martyred in 363. In 1203 Pope Innocent III had the cathedral moved within the city's walls, in the current site. The Cathedral, however, lost the relics of Donatus, which were transferred in the church of San Donato in Castiglione Messer Raimondo (in what is now the province of Teramo). In spite of this, the church is still entitled to St. Donatus and houses, at the high altar, a 14th century arch named after him.
The construction of the current structure, started in 1278, went through different phases, and ended in 1511. The façade was built in 1901-1914, replacing the previous, unfinished one, dating to the 15th century.
It was the seat of the Bishop of Arezzo from the 3rd century until 1986, and from 1986 onwards of the present Bishop of Arezzo-Cortona-Sansepolcro.