After his brother's defeat and capture by the Bulgarians at the Battle of Klokotnitsa in 1230, Manuel was allowed by Ivan Asen II to rule in Thessalonica and its environs with the title of despotes.

At one point Manuel attempted to make contact with the papacy, but in 1232 the longstanding rift with the Eastern Patriarchate in Nicaea was finally healed.

In 1235, Manuel joined forces with the Nicaeans and Bulgarians in the siege of Constantinople by John Duka Vatatses and Tsar Ivan Asen II.

Manuel ruled until 1237, when his widowed father-in-law Ivan Asen II married Irene, the daughter of the imprisoned Theodore.

Manuel was unsuccessful in his efforts to gain the support of Prince Geoffrey II Villehardouin of Achaea and was forced to flee to Asia Minor.