In 1510 he was elected Bishop of Sovana, a suffragan of the Archdiocese of Siena,[1] but resigned the See in July 1513 in favor of his relative, Lattanzio Petrucci.

[2] In March 1511 he was created Cardinal-Deacon of S. Teodoro pro hac vice by Pope Julius II.

He attended the Fifth Council of the Lateran in February 1513,and so was already in Rome when Pope Julius died.

At the conclave of 1513 he was among the younger cardinals that supported Giovanni de'Medici, who was elected Pope Leo X. Pandolfo Petrucci died in 1512 and was succeeded as governor of Siena by Alfonso's brother Borghese.

In March 1516, Leo replaced Borghese with his cousin Raffaello Petrucci, a long-time friend.