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. 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 of 1503 in order to appease Borgia. He subsequently resided in Lucca. With the assistance of his ally King Louis XII of France, 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. In return, the pope made Petrucci’s nephew a cardinal. Later that year, Petrucci handed control of Siena over to his son, Borghese, and died shortly afterwards in San Quirico d'Orcia, Italy. Before his death, Petrucci was known to have plotted in secret with Spain and Pope Julius II against his old allies, the French. He was also rumoured to have had Pope Pius III poisoned in 1503.
Following Pandolfo’s death, the Petrucci family ruled Siena until 1524.