In April of the next year, Emperor John entered Veria with the help of Stephen Dushan and appointed Manuel as governor of the city.
[1] 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.
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.
"[3] For the larger portion of his reign, Manuel maintained peaceful relations with his Latin neighbors and secured a long period of prosperity for the area.
The Aragonese version of the Chronicle of the Morea states that, in alliance with Gautier de Lor, the Venetians, and the Hospitallers, he scored a naval victory over a Turkish fleet off Megara, setting fire to 35 of the enemy ships; the survivors then fled to Roger of Lluria at Thebes.
After John achieved victory in the subsequent civil war, Manuel took pains to point out no vows had been made in this second engagement, so his marriage to Isabelle would not be irregular.