Upon Bayezid II's accession to the throne, he entered the state service and served as a judge in Sofia, Silivri, Galata, and, in 1499, Seres.

He won the appreciation of Sultan Selim with his words about attacking immediately without waiting in a war council.

He was thereupon appointed as the Istanbul guard and governor of the sedaret after Yavuz Sultan Selim's departure to Egypt with the Ottoman army in 1516.

[6] Piri Mehmed Pasha, who was the guard of Istanbul, equipped the fleet to be sent to Alexandria with great care.

All these works and efforts of Piri Mehmed Pasha were preparing him for the position of grand vizier in the eyes of Yavuz Sultan Selim.

Upon his return from the Egypt Campaign, Yavuz Sultan Selim had Yunus Pasha, who was the grand vizier, executed on September 13, 1517, with a sudden decision.

Piri Mehmed Pasha reached the camp in Damascus on January 24, 1518, and was appointed to the position of grand vizier the next day.

[4] He constantly persuaded the new sultan that Belgrade should be conquered, and he advocated the view that its conquest should be given priority.

[4] Ahmed Pasha (Hain, "Traitor"), his rival who would later have a role in Piri's dismissal, suggested taking first Šabac, then cross the Sava and strike Buda.

[9] The sultan then ordered Piri to lift the siege in Belgrade and join the bulk of the army as he started to build a bridge to cross the Sava.

[4][13][additional citation(s) needed] He played an important role in the capture of Rhodes, but Ahmed Pasha put pressure on the sultan, and upon his return from the expedition an investigation started against him for allegedly receiving bribery.

[4][additional citation(s) needed] He was found guilty by the Rumelian and Anatolian kazaskers, and it is said that Ahmed Pasha had to do with the verdict as well.

Ibrahim Pasha traveled south to Egypt in 1525 and reformed the Egyptian provincial civil and military administration system.

[14][15] Ibrahim Pasha then returned to Istanbul after a major administrative and financial reforms in the Egyptian province.

It is rumored that Piri Mehmed Pasha, who retreated to his farm in Silivri after retiring from the Grand Viziership, visited the palace very often and even had a good relationship with Suleiman.

The fact that he was appointed grand vizier and served as such for a long time is witness to his abilities.

He was educated in the ilmiye, and yet displayed military skills, playing an important role in the Ottoman successes of the day.

In Silivri, where he retired and died, he has a complex consisting of a mosque, soup kitchen (Imaret), school and madrasah, and his tomb is located here.