The Ottomans under Piyale Pasha's command overwhelmed a large joint Christian alliance fleet, composed chiefly of Spanish, Papal, Genoese, Maltese, and Neapolitan forces.

[5] Until about 1573 the Mediterranean headed the list of Spanish priorities under Philip II of Spain (1556–98); under his leadership the Habsburg galley fleet increased to about 100 ships, and more in wartime.

[clarification needed][6] Since losing against Barbarossa Hayreddin's Ottoman fleet at the Battle of Preveza in 1538 and the disastrous expedition of Emperor Charles V against Barbarossa in Algiers in 1541, the major European sea powers in the Mediterranean, Spain and Venice, felt more and more threatened by the Ottomans and their corsair allies.

King Philip II of Spain appealed to Pope Paul IV and his allies in Europe to organize an expedition to retake Tripoli from Turgut Reis, who had captured the city from the Maltese Knights in August 1551 and had subsequently been made Bey (Governor) of Tripoli by Sultan Suleiman the Magnificent.

The historian William H. Prescott wrote that the sources describing the Djerba campaign were so contradictory it was impossible to reconcile them.

Although the expedition landed not far from Tripoli, the lack of water, sickness and a freak storm caused the commanders to abandon their original objective, and on 7 March they returned to the island of Djerba, which they quickly overran.

The Viceroy of Sicily, Juan de la Cerda, 4th Duke of Medinaceli, ordered a fort to be built on the island, and construction was begun.

There is a claim that the victorious Ottomans erected a pyramid of skulls of the defeated Spanish defenders, which stood until the late nineteenth century.

[16] The Battle of Djerba is given a prominent place in The Course of Fortune by Tony Rothman (2015), a novel that concerns the events leading to the Great Siege of Malta, 1565.