Manuel Kantakouzenos (or Cantacuzenus) (Greek: Μανουήλ Καντακουζηνός, Manouēl Kantakouzēnos), (c. 1326 – Mistra, Peloponnese, 10 April 1380). Despotēs in the Despotate of Morea or the Peloponnese from 25 October 1349 to his death and a contender to the Principality of Achaia.
Manuel Kantakouzenos was the second son of Emperor John VI Kantakouzenos and Irene Asanina. Donald Nicol believes he was born around 1326 or slightly later.
Manuel is first mentioned in March 1342 when he and his brother Matthew Kantakouzenos accompanied his father from Didymoteichos for Thessalonica as officers. In April of the next year, Emperor John entered Veria with the help of Stephen Dushan and appointed Manuel as governor of the city. In June 1345 supporters of his father seized control of Thessalonica and sent an appeal of help to Manuel, but the army he sent arrived too late to save the situation. In 1347 Stephan Dushan seized Veria from Manuel, forcing the former to seek refuge with his uncle John Komnenos Doukas in Thessaly. After his father took control of Constantinople in May 1347, he sent for Manuel to come to the city, and the following year he entrusted Manuel with its government. As Prefect of the City, Manuel led its defense against the Genoese in the war of 1348–1349.
At the conclusion of the war with Genoa, Manuel was named governor of Morea by his father, and arrived in his province on 25 October 1349. Manuel was the first of a series of long-ruling governors of the province who bore the title of despotēs and were closely related to the emperors at Constantinople. Manuel established order in his province by crushing the opposition of local notables (Archontes). His success was such that when John VI Kantakouzenos was forced to abdicate by his son-in-law John V Palaiologos, Manuel was able to resist the attempt to replace him as governor by the emperor's appointees. Eventually Manuel was recognized as governor of Morea by the new regime. Following the abdication of his father John Kantakouzenos, who was now the monk Josaph, the rest of his family joined Manuel in the Morea. Some of Manuel's enemies circulated a rumor that his older brother, the former Emperor Matthew Kantakouzenos, plotted to replace him as governor, but when he was persuaded the rumor was false, the two worked together in the administration of the province, although Nicol observes "Matthew played no more than a secondary role."