His conduct during his youth was so violent that, after the death of his father Michael in 1320, his grandfather Andronicus II resolved to deprive him of his right to the crown. Andronicus rebelled; he had a powerful party, and the first period of civil war ended in his being crowned and accepted as colleague by his grandfather, 1325. The quarrel broke out again and, notwithstanding the help of the Bulgarians, the older emperor was compelled to abdicate in 1328.
His chief minister during this period was John Cantacuzenus, later Emperor John VI. During his reign Andronicus III was engaged in constant war, chiefly with the Ottoman Turks, who greatly extended their territory, conquering almost all of Asia Minor before his coming to power. Under Andronicus's rule, Nicaea fell to Ottoman emir Orhan I in 1331, with Nicomedia following in 1337. After that, in Asia Minor only Philadelphia and a handful of ports remained under Byzantine control. He annexed large regions in Thessaly and Epirus, but they were lost few years after his death in period of new civil war to the rising power of Serbia under Stefan Dusan. Andronicus worked on the reorganization of the navy, and recovered Lesbos, Phocaea, and Chios from the Genoese. He died in 1341, and was succeeded by his son, John V.