In August 1551, the Ottoman Turks, under naval commander Turgut Reis, and Barbary pirates besieged and vanquished the Knights of Malta in the Red Castle of Tripoli, which had been a possession of the Knights of Malta since 1530. The siege culminated in a six-day bombardment and the surrender of the city on 15 August.

In 1553, Turgut Reis was nominated commander of Tripoli by Suleiman, making the city an important center for piratical raids in the Mediterranean and the capital of the Ottoman province of Tripolitania. In 1560, a powerful naval force was sent to recapture Tripoli, but that force was defeated in the Battle of Djerba.

The siege of Tripoli succeeded an earlier attack on Malta in July, which was repelled, and the successful invasion of Gozo, in which 5,000 Christian captives were taken and brought on galleys to the location of Tripoli.