After establishing himself as the Despot, Constantine worked to strengthen the defense of Morea, including reconstructing a wall across the Isthmus of Corinth called the Hexamilion, "the Six Mile Wall."
In the summer of 1444, he launched an invasion of the Latin Duchy of Athens from Morea, swiftly conquering Thebes and Athens and forcing its Florentine duke to pay him tribute. The Duchy was ruled by Nerio II Acciajuoli, a vassal of the Ottoman Sultan.
However, his triumph was short-lived. In the fall of 1446, the Ottomans advanced on Morea with 50-60,000 soldiers. Constantine and his brother Thomas braced for the attack at the Hexamilion, which the Ottoman army reached on November 27, 1446. While the wall may have held against medieval attacks, Sultan Murad had cannons to supplement the usual siege engines and scaling ladders, leaving the Hexamilion in ruins by December 10. Constantine and Thomas barely escaped. The winter prevented a full conquest of Morea, and Murad left that to another day, but put an end to Constantine's attempt to expand his Despotate.
When his brother, Emperor John VIII Palaiologos, died, a dispute erupted between Constantine and his brother Demetrios Palaiologos over the throne. Demetrios drew support for his opposition to the union between the Orthodox and Catholic churches. The Empress Helena, acting as regent, supported Constantine. They appealed to the Ottoman Sultan Murad II to arbitrate the disagreement.
Murad chose Constantine, who was crowned at Mistra on January 6, 1449. It was unusual to crown an emperor outside of Constantinople (and without a Patriarch of the Orthodox Church), and no ecclesiastical coronation was ever performed. Constantine was forced to seek passage to his capital on a Catalan ship, arriving in March 1449. Constantine XI attempted to marry a distant cousin, Maria Branković, the widow of Murad II, but the courtship failed.
Sultan Murad died in 1451, succeeded by his 19 year old son Mehmed II. Soon afterwards, Mehmed II began agitating for ownership of Constantinople. Constantine threatened to release Prince Orhan, a pretender to the Ottoman throne, unless Mehmed doubled an annual payment. To Mehmed, this was the last straw, and he considered Constantine to have broken the truce. The following winter of 1451-52, Mehmed built Rumelihisari, a fortress on a hill at the European side of the Bosporus, just north of the city, as a prelude for a siege.
Desperate for any type of military assistance, Constantine XI appealed to the West and reaffirmed the union of Eastern and Roman Churches which had been signed at the Council of Florence. However, the union was overwhelmingly rejected by his subjects and it dangerously estranged him from Loukas Notaras, his chief minister and military commander. Although some troops did arrive from the mercantile city states in the north of Italy, the Western contribution was not adequate to counterbalance Ottoman strength. While Constantine also sought assistance from his brothers in Morea, any help was forestalled by an Ottoman invasion of the peninsula in 1452. The siege of the city began in the winter of 1453.
Instead he led the defence of the city and took an active part in the fighting along the land walls. At the same time, he used his diplomatic skills to maintain the necessary unity between the Genovese, Venetian, and Greek troops.
As the city fell on May 29 1453, Constantine is said to have remarked: "The city is fallen but I am alive". Realising that the end had come, he reportedly discarded his purple cloak and led his remaining soldiers into a last charge where he was killed.
A legend tells that when the Ottomans entered the city, an angel rescued the emperor, turned him into marble and placed him in a cave under the earth near the Golden Gate, where he waits to be brought to life again .
Constantine XI legacy was used as a rallying cry for Greeks during their war for Independence from the Ottoman empire. Today the Emperor is considered a national hero in Greece