There was already a cathedral on the site (on the present Via Indipendenza) in 1028, accompanied by a pre-Romanesque campanile with a circular base (in the architectural tradition of Ravenna).

From about 1477 the Ferrarese painters Francesco del Cossa and Ercole de' Roberti worked in the Garganelli Chapel on the creation of a cycle of frescoes which later had a significant influence on Niccolò dell'Arca and Michelangelo.

By order of Cardinal Gabriele Paleotti a radical remodelling of the interior of the building began in 1575, of which the crypt and the Greater Chapel (Capella Maggiore) survive.

The alterations were so extensive however as to cause the vaults to collapse in 1599, and the decision was then made to rebuild the main part of the cathedral from scratch.

Among the works of art are an Annunciation by Ludovico Carracci (a fresco in the central lunette of the presbytery), a Romanesque Crucifixion in cedarwood, and a sculptured group in terracotta depicting the Compianto su Cristo morto ("Lament over the Dead Christ"), by Alfonso Lombardi, of the early 16th century.