Born and raised in Siena, Petrucci spent a great part of his life in exile, but on the triumph of the Noveschi party he was able to return home in 1487. He later became captain of the city guard. When his powerful brother Giacopo died in 1479, Pandolfo assumed all of his offices and seized control of his fortune. His power and wealth increased even further with his marriage to Aurelia Borghese, daughter of the powerful Niccolò Borghese. But he soon began to abuse his power by selling public offices to the highest bidder or giving them to his followers. However, Petrucci's power and his organization of followers in Siena's government gained him many enemies, including his father-in-law. Niccolò and other influential citizens of Siena conspired to assassinate him, but Petrucci uncovered the plot and had Niccolò murdered in 1500.
With his enemies out of the way, Petrucci ruled as absolute tyrant over Siena. Petrucci subsequently stopped selling public offices in order to consolidate his own power. Although a brutal authoritarian and absolutist, Petrucci was careful to pacify the people of Siena by improving the city's economy and encouraging the advancement of art. He also managed to avoid a war with Florence, which had been at odds with Siena for over a century due to a dispute over Siena's control of Montepulciano. When France and Spain invaded the Italian Peninsula, Petrucci became involved in a number of political intrigues. During this time period, Petrucci tried to gain the powerful Cesare. Borgia's trust by diplomatically procuring French-controlled Piombino for Borgia. However, he secretly plotted against Borgia in the hopes of increasing his own power, and had one of his most trusted friends and confidant, Antonio da Venafro, attend the Diet of La Magione in September 1502. Borgia, who had never trusted Petrucci, learned of the Sienese tyrant's plans and invited him to a meeting at Senigallia in 1502, where Petrucci would have been executed along with Cesare's other enemies. Petrucci suspected his life was in danger and avoided the meeting, but nevertheless fled Siena in January, 1503, in order to appease Borgia. With the assistance of his ally King Louis XII, however, Petrucci was returned to power two months later. With Borgia's death in 1507, Petrucci became one of the most powerful men in Italy. In his final years, Petrucci supported Pisa militarily in its war against Florence. However, Pope Julius II and Spain obliged Petrucci to make peace with Florence, to which he reluctantly gave the territory of Montepulciano in 1512. Petrucci was known to have plotted in secret with Spain and Pope Julius II against his old allies, the French. He was also rumored to have had Pope Pius III poisoned in 1503. He died in San Quirico d'Orcia on May 21, 1512.