The second Siege of Rhodes marked a significant military endeavor by the Ottoman Empire, striving to conquer an important strategic stronghold in the Aegean Sea. The Knights Hospitaller, a religious and military order, had successfully held the island since 1291. The Ottomans, under the command of Grand Vizier Piri Mehmed Pasha, sought to assert their dominance in the region following their earlier unsuccessful attempt to capture Rhodes in 1480. The importance of Rhodes lay not only in its geographical position on the trade routes between Europe and the Middle East but also as a base for Christian maritime operations against Ottoman shipping.

Beginning in June 1522, the Ottomans deployed a formidable force that included both a substantial naval fleet and a diverse army consisting of janissaries, artillery, and local allies. The Ottomans' strategy relied heavily on their naval superiority, which allowed them to lay siege to the island from both land and sea. The Knights, led by Grand Master Philippe Villiers de L’Isle-Adam, were resolute in their defense, utilizing the city’s fortified walls and engaging in fierce combat against the besieging forces.

As the siege progressed, the defenders faced overwhelming odds, including dwindling supplies and increasingly powerful Ottoman artillery. Despite their strong resolve and strategic defenses, the situation for the Knights grew dire as the months passed, highlighting the challenges of maintaining a prolonged siege in the face of a determined and well-equipped adversary. The fall of Rhodes would eventually come, marking a pivotal point in the turbulent relations between the Christian and Muslim worlds during this period.