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Manuel Kantakouzenos or Cantacuzenus (Greek: Μανουήλ Καντακουζηνός, Manouēl Kantakouzēnos), (c. 1326–April 10, 1380. Despot (despotēs) in the Despotate of Morea from October 25, 1349 to his death.

Manuel Kantakouzenos was the second son of Emperor John VI Kantakouzenos by Eirene Asanina. His maternal grandfather was Andronikos Asan. Andronikos was a son of Ivan Asen III of Bulgaria and Eirene Palaiologina. Eirene was herself a daughter of Michael VIII Palaiologos and Theodora Doukaina Vatatzina.

Manuel had served as governor of Veria and Constantinople in the mid-1340s. In 1348 he was named governor of Morea by his father, and arrived in his province in 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. Secure in his rule, Manuel maintained peaceful relations with his Latin neighbors and secured a long period of prosperity for the area. Greeco-Latin cooperation included an alliance to contain the raids of Murad I into Morea in the 1360s. Moreover, Manuel encouraged the immigration of Albanians to settle in the depopulated province as a source of economic and military manpower.

Manuel Kantakouzenos had married Isabelle of Lusignan, a daughter of Guy of Lusignan (King Constantine II or IV of the Armenian Kingdom of Cilicia) but left no male heir. On his death in 1380, he was succeeded as governor by his older brother, the former Emperor Matthew Kantakouzenos.

• The Oxford Dictionary of Byzantium, Oxford University Press, 1991.