As a Knight Hospitaller, joining the order in the Langue de Provence, he fought with distinction against the Turks at Rhodes. As Grand Master, Valette became the Order’s hero and most illustrious leader, commanding the resistance against the Ottomans at the Great Siege of Malta in 1565, sometimes regarded as one of the greatest sieges of all time.
The foundation stone of Valletta was laid by Grandmaster La Valette in 1566. He did not live to see Valletta completed, as he died in 1568 and was succeeded by Grandmaster Pierre de Monte.