The Spanish Habsburgs had established a fort in Tripoli, modern Libya, in 1510 under Charles V, and remitted it the Knights of Malta in 1530.

The city is under the command of Father Gaspard de Vallier, with thirty knights (some authors say two hundred) and six hundred and thirty Calabrian and Sicilian mercenaries.

The Ottomans had had a base since 1531 in the city of Tajura, twenty kilometers to the east, where Khayr al-Din Barbarossa had been based.

The Ottomans encircle the fort at the beginning of August 1551, and establish three batteries of twelve guns each.

The Ottoman Siege of Tripoli is the first step of the all-out Italian War of 1551–59 in the European theater.

The French galleys of Marseilles are ordered to join the Ottoman fleet.

The French Ambassador to the Ottoman Empire, Gabriel de Luetz, Baron et Seigneur d'Aramon et de Vallabregues (often also abbreviated to Gabriel d'Aramon), joins the Ottoman fleet at Tripoli, with two galleys and a galliot.

The declared mission of the ambassador is to dissuade the Ottomans from capturing the city, at the request of the Grand Master of Malta, as Malta had not been identified as an enemy in the Franco-Ottoman alliance against the Habsburgs.

According to later reports, when Sinan Pasha and Dragut refused to lift the siege, on grounds that they were under order to eradicate the Knights of Malta from the African continent, d'Aramon threatened to sail to Constantinople to appeal to Suleiman, but he was then barred from leaving the city until the end of the siege.

Soon the soldiers in the fort mutiny, and negotiations for surrender start.

The siege, which culminates in a six-day bombardment and the surrender of the city to Sinan Pasha on August 15, succeeds an earlier attack on Malta in July, which the Knights had repelled, and the successful Invasion of Gozo, in which five thousand or more Christian captives had been taken and brought on galleys to the location of Tripoli.

The Knights, many of them French, are returned to Malta upon the intervention of the French ambassador, shipped onboard his galleys, while the mercenaries are enslaved.

Murād Agha, the Ottoman commander of Tajura since 1536, is named as the Pashalik of the city.

Nicolas de Villegagnon, the future explorer of Brazil, is present at the siege, and will write an account about it in 1553.