The church, an example of Renaissance Greek cross central plan, was designed by Antonio da Sangallo the Elder, who was inspired by the Basilica of Santa Maria delle Carceri in Prato, which had been designed years before by his brother Giuliano da Sangallo. The same plan, taken from Filippo Brunelleschi's works, was used for the original design by Bramante and Michelangelo for St. Peter's Basilica, as well as for the church of Santa Maria della Consolazione in Todi, of uncertain paternity.
The late Renaissance building was constructed on the site of a pre-existing Palaeochristian pieve dedicated to St. Mary and subsequently to St. Blaise. In the early 16th century only remains existed of the pieve, including a wall with a fresco of Madonna with Child and St. Francis, from a 14th century Sienese painter. The project was supported by Pope Leo X, who had studied under Angelo Poliziano, a native of Montepulciano.
The construction lasted until 1580 and, after Sangallo's death, was directed by other superintendents.