Following the accession to the throne of Suleiman I, the sultan sent an ambassador to Louis II to collect the annual tribute that Hungary had been subjected to. Louis refused to pay the annual tribute and had the Ottoman ambassador executed and sent the head to the Sultan. Louis believed that the Papal States and other Christian States including Charles V, Holy Roman Emperor would help him. This event hastened the fall of Hungary.

Hungary was in a state of near anarchy in 1520 under the rule of the magnates. The king's finances were a shambles; he borrowed to meet his household expenses despite the fact that they totaled about one-third of the national income. The country's defenses weakened as border guards went unpaid, fortresses fell into disrepair, and initiatives to increase taxes to reinforce defenses were stifled. In 1521 Sultan Suleiman the Magnificent was well aware of Hungary's weakness.

The Ottoman Empire declared war on the Kingdom of Hungary, Suleiman postponed his plan to besiege Rhodes and made an expedition to Belgrade. Louis and his wife Mary requested military aid from other European countries. His uncle, King Sigismund of Poland, and his brother-in-law, Archduke Ferdinand, were willing to help. Ferdinand dispatched 3,000 infantry troops and some artillery while preparing to mobilize the Austrian estates, while Sigismund promised to send footmen. The coordination process totally failed though. Mary, although a determined leader, caused distrust by relying on non-Hungarian advisors while Louis lacked vigour, which his nobles realized.

Belgrade and many strategic castles in Serbia were captured by the Ottomans. This was disastrous for Louis' kingdom; without the strategically important cities of Belgrade and Šabac, Hungary, including Buda, was open to further Turkish conquests.