Andrea II is known for having expanded the Principality of Muzaka to its greatest extent, from the southern Adriatic coastline of Albania in the west to Kastoria in the east by the time of his death in 1372.

During his wars against the Serbian successor states, Andrea II succeeded in defeating both Vukašin of Serbia and his son, Prince Marko, solidifying his family's principality.

His grandfather, Andrea I Muzaka, established de facto independent territorial rule around 1280 in the Myzeqe region west of Berat, which was later named after the family.

Andrea II led the resistance against the Serbs and formed various alliances with other Albanian noble families, as well as maintaining ties with his traditional Angevin allies.

[7] In 1350, Andrea II seized Berat from the Serbians, which forced John Komnenos Asen, the local lord appointed by Stefan Dušan to govern the region, to move his seat to Kanina.

[5] After the death of Stefan Dušan in 1355 and the collapse of the short-lived Serbian Empire, Andrea II regained control over parts of south-eastern modern-day Albania and significantly expanded the principality.

In the late 1360s, Andrea II was engaged in a conflict over the southwestern provinces of Macedonia (including Kastoria) against Vukašin Mrnjavčević, the King of Serbia.

[11][12] As a result of this battle, the Byzantine Emperor John V Palaiologos presented Andrea II with the imperial emblem, and granted him the title of "despot of Epirus".

[15] At its greatest extent, just before Andrea II's death, his expansion of the principality covered the regions of Myzeqe, Berat, Tomorricë, Skrapar, Këlcyrë, Përmet, Opar, Devoll, Kolonjë and Kastoria.