Theodore II's enemies in that period included the Republic of Venice, which sent troops to impede his attempt to conquer Patras.

During Theodore's minority, his father Emperor Manuel II stayed in Morea and supervised its administration and defense, rebuilding the Hexamilion wall across the Isthmus of Corinth.

A moment of drastic change in policy was his marriage to the Latin noblewoman Cleofa Malatesta, arranged with the help of her uncle Pope Martin V, who became Theodore's ally and supporter.

The war in Morea had started to go against the Byzantines and, under pressure from Carlo I Tocco, the Count of Kefalonia and ruler of Epirus, the Despot demanded help from his brother John VIII.

In a compromise, Theodore II Palaiologos surrendered his claim to the throne in exchange for Constantine's domain (appanage) of Selymbria (Silivri) in 1443, where he died of plague five years later, in 1448, predeceasing his brothers.