Donatello's equestrian statue of Gattamelata (1453) is visible in front of the church.

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.