In 1394 the northern of the two bell-towers flanking the sixth dome collapsed on to the ambulatory. The old rectangular towers were replaced by the present, taller, octagonal ones, and the ambulatory was rebuilt, considerably raised in height. In 1424 the choir was given its segmental vault, and the seventh external dome was built above it. The axial ambulatory chapel was replaced in 1689-1697 by the circular Tesoro Chapel, which added an eighth dome.

The cult of St Anthony, famous as a preacher in his lifetime, grew enormously following his canonization in 1232. A project for a new structure dedicated to the saint is documented in 1238. In 1263 the body of St Anthony was translated into the centre of the new church. The earlier church of S Maria Mater Domini was partially retained as a chapel flanking the short transept. In 1310 St Anthony's body was again translated, probably to the chevet, possibly to allow for the construction of the third dome. In 1350 it was moved to its final location in the north arm of the larger, western transept. The initial covering of six domes had been completed by c. 1330.