Piero returned to his hometown in 1442 and was elected to the City Council of Sansepolcro.
Three years later, he received his first commission, to paint the Madonna della Misericordia altarpiece for the church of the Misericordia in Sansepolcro, which was completed in the early 1460s.
In 1449 he executed several frescoes in the Castello Estense and the church of Sant'Andrea of Ferrara, now also lost.
His influence was particularly strong in the later Ferrarese allegorical works of Cosimo Tura.

The Baptism of Christ, now in the National Gallery in London, was completed in about 1450 for the high altar of the church of the Priory of S. Giovanni Battista at Sansepolcro.
Other notable works are the frescoes of The Resurrection in Sansepolcro, and the Madonna del parto in Monterchi, near Sansepolcro.

Two years later he was in Rimini, working for the condottiero Sigismondo Pandolfo Malatesta.
In 1451, during that sojourn, he executed the famous fresco of St. Sigismund and Sigismondo Pandolfo Malatesta in the Tempio Malatestiano, as well as a portrait of Sigismondo.
In Rimini, Piero may have met the famous Renaissance mathematician and architect Leon Battista Alberti, who had redesigned the Tempio Malatestiano, although it is known that Alberti directed the execution of his designs for the church by correspondence with his building supervisor.
Thereafter Piero was active in Ancona, Pesaro and Bologna.

In 1454, he signed a contract for the Polyptych of Saint Augustine in the church of Sant'Agostino in Sansepolcro.
The central panel of this polyptych is lost, and the four panels of the wings, with representations of saints, are now scattered around the world.
A few years later, summoned by Pope Nicholas V, he moved to Rome, where he executed frescoes in the Basilica di Santa Maria Maggiore, of which only fragments remain.
Two years later he was again in the Papal capital, painting frescoes in the Vatican Palace, which have since been destroyed.
Piero returned to his hometown in 1442 and was elected to the City Council of Sansepolcro. Three years later, he received his first commission, to paint the Madonna della Misericordia altarpiece for the church of the Misericordia in Sansepolcro, which was completed in the early 1460s. In 1449 he executed several frescoes in the Castello Estense and the church of Sant'Andrea of Ferrara, now also lost. His influence was particularly strong in the later Ferrarese allegorical works of Cosimo Tura.
The Baptism of Christ, now in the National Gallery in London, was completed in about 1450 for the high altar of the church of the Priory of S. Giovanni Battista at Sansepolcro. Other notable works are the frescoes of The Resurrection in Sansepolcro, and the Madonna del parto in Monterchi, near Sansepolcro.
Two years later he was in Rimini, working for the condottiero Sigismondo Pandolfo Malatesta. In 1451, during that sojourn, he executed the famous fresco of St. Sigismund and Sigismondo Pandolfo Malatesta in the Tempio Malatestiano, as well as a portrait of Sigismondo. In Rimini, Piero may have met the famous Renaissance mathematician and architect Leon Battista Alberti, who had redesigned the Tempio Malatestiano, although it is known that Alberti directed the execution of his designs for the church by correspondence with his building supervisor. Thereafter Piero was active in Ancona, Pesaro and Bologna.
In 1454, he signed a contract for the Polyptych of Saint Augustine in the church of Sant'Agostino in Sansepolcro. The central panel of this polyptych is lost, and the four panels of the wings, with representations of saints, are now scattered around the world. A few years later, summoned by Pope Nicholas V, he moved to Rome, where he executed frescoes in the Basilica di Santa Maria Maggiore, of which only fragments remain. Two years later he was again in the Papal capital, painting frescoes in the Vatican Palace, which have since been destroyed.
Piero della Francesca