Mystras became the seat of the Latin Despotate of Morea, a vassal state of the Latin Principality of Achaea, established in 1205 after the conquest of Constantinople during the Fourth Crusade. Prince William II Villehardouin, a grand-nephew of the Fourth Crusade historian Geoffrey of Villehardouin, built a palace there in 1249.
Mystras was also the last centre of Byzantine scholarship; the Neoplatonist philosopher George Gemistos Plethon lived there until his death in 1452. He and other scholars based in Mystras influenced the Italian Renaissance, especially after he accompanied the emperor John VIII Palaeologus to Florence in 1439.
The last Byzantine emperor, Constantine XI, was despot at Mystras before he came to the throne. Demetrius, the last despot of Morea, surrendered the city to the Ottoman emperor Mehmed II in 1460. The Venetians occupied it from 1687 to 1715, but otherwise the Ottomans held it until 1832, when it was abandoned by King Otto for the newly rebuilt Sparta.