When Constantine II was killed in an uprising in 1344, Constantine III succeeded him. He attempted to wipe out all rival claimants to the throne; he gave orders to kill Constantine II's nephews, Bemon and Leo, but before the murder could be carried out they escaped to Cyprus. During his rule, Armenian Kingdom of Cilicia was reduced by Mamluk raids and conquests. They conquered Ajazzo in 1347, Tarsus and Adana in 1359.
Constantine was the first husband of Maria, daughter of Oshin of Corycos and Jeanne of Anjou. He was predeceased by his two sons. Upon his death from natural causes he was succeeded by his cousin Constantine IV.