Medieval historians refer to this place as that of a Roman temple dedicated to the Bona Mater. Saint Peter Damian wrote that on this site there was a basilica containing the remains of Saint Rufinus, dating back to 412, and that Bishop Hugo (11th century) was at odds with the people because he wanted to take it to the then Cathedral of Santa Maria Maggiore with the victory of the citizens of Assisi.
In the feudal city, the church of San Rufino was the fulcrum of the "citadel of the canons" and the foundation of the current church probably dates back to the eighth century. It was rebuilt for the first time in a larger form by Hugo himself, who gave it the title of cathedral in 1036. In 1140 a new reconstruction was started, based on a project by Giovanni da Gubbio, which lasted several decades. In 1210, the community, which used the churchyard for meetings, hoped for a speedy completion, attributing to the unfinished building the bad luck that animated the fighting between the factions. In 1228, the high altar was consecrated by Pope Gregory IX and in 1253 the entire church was consecrated by Innocent IV. In 1571, the interior of the cathedral was renovated according to a design by Galeazzo Alessi and took on its current form.