The Venetian interest in Cyprus was inspired solely by profit. The Venetians saw Cyprus mainly as a military base. Anticipating the conflict, they embarked on an ambitious fortification plan. Famagusta and Nicosia were surrounded by massive earthworks, covered with stone. An external wall was erected around the castle of Kyrenia, the void of which was filled with earth to form an artillery bastion. The best military architects in Europe were brought to the island to design and execute these projects.

Cypriots were seen as a people to be taxed as much as possible. The island was well equipped with the essential timber for shipbuilding and was an ideal base from which the Venetians could dominate trade with the East. They continued to pay the homage paid to Cyprus by the Mamelukes and, when the latter were conquered by the Ottomans, the tribute was redirected to Constantinople, the seat of Ottoman power since 1453.

Taking the lead of the Ottoman Empire from his father, Sultan Selim II repeatedly complained to the Venetians and called for an end to piracy in the seas surrounding Cyprus. The Venetians refused to do so and ignored the Sultan's request for full control of the island.

These relations were exacerbated by the Venetian seizure of Turkish ships, by the execution of Turkish corsairs in violation of an Ottoman-Venetian treaty and by the continuous presence of Maltese pirates in the Venetian ports that harassed Muslim pilgrims and interfered in general trade. Therefore, the Sultan decided to intervene and put an end to this state of affairs, as well as to consolidate Ottoman control of the East in general. In 1570, after an ultimatum expired, hordes of Ottoman troops landed in Larnaca, under Lala Mustapha Pasha. Nicosia was besieged and resisted for six weeks, rejecting terms of honourable surrender on the rumours of an approaching Venetian fleet. The city was eventually stormed and plundered and 20,000 inhabitants were massacred. Kyrenia capitulated without a fight.

In October, Lila Mustapha Pasha with an army of 200,000 men began the siege of Famagusta. The besieged part received little reinforcements in January 1571, when the Turkish fleet withdrew its winter anchor, but after ten months the garrison was reduced to 1500 men, while 80,000 Ottoman soldiers had died. On August 1st, the terms of capitulation were agreed between the captain of Famagusta, Marco Antonio Bragadino, and Lala Mustapha Pasha. However, a dispute arose and some careless words of Bragadino led him to be skinned alive. Despite a naval reversal in Lepanto, on the Adriatic coast, on 7 October 1571, Selim's efforts were successful and the Venetians had to negotiate for peace.

Later that month, Venetian officials delivered the island together with 300,000 ducats for war repair.