Initially, he was awarded the title of despot in 1346, and appointed governor of southern Epirus and Acarnania in 1347 by his half-brother, Serbian Emperor Stephen Dušan.

That led him to conflict with his nephew in 1356, when Simeon started to expand his control in southern regions of the Empire, trying to take Thessaly and Macedonia.

He proclaimed himself Emperor of the Serbs and Greeks, creating a separate state, centered in regions of Thessaly and Epirus, where he ruled until his death in 1370.

After he was forced to retreat from his attempt to invade Zeta (modern Montenegro) in 1358, Simeon Uroš gave up hope of asserting himself in Serbia.

While Simeon Uroš was in Epirus, Radoslav Hlapen of Vodena (Edessa) attempted to seize Thessaly on behalf of his stepson Thomas Preljubović.

Simeon Uroš was forced to cut his losses by recognizing Radoslav Hlapen's conquests, turning over Kastoria to him, and marrying his daughter Maria to Thomas.