The Byzantine civil war of 1341–1347, sometimes referred to as the Second Palaiologan Civil War, was a conflict that broke out in the Byzantine Empire after the death of Andronikos III Palaiologos over the guardianship of his nine-year-old son and heir, John V Palaiologos. It pitted on the one hand Andronikos III's chief minister, John VI Kantakouzenos, and on the other a regency headed by the Empress-Dowager Anna of Savoy, the Patriarch of Constantinople John XIV Kalekas, and the megas doux Alexios Apokaukos. The war polarized Byzantine society along class lines, with the aristocracy backing Kantakouzenos and the lower and middle classes supporting the regency. To a lesser extent, the conflict acquired religious overtones; Byzantium was embroiled in the Hesychast controversy, and adherence to the mystical doctrine of Hesychasm was often equated with support for Kantakouzenos.

As the chief aide and closest friend of Emperor Andronikos III, Kantakouzenos became regent for the underage John V upon Andronikos's death in June 1341. While Kantakouzenos was absent from Constantinople in September the same year, a coup d'état led by Alexios Apokaukos and the Patriarch John XIV secured the support of Empress Anna and established a new regency. In response, Kantakouzenos' army and supporters proclaimed him co-emperor in October, cementing the rift between himself and the new regency. The split immediately escalated into armed conflict.

During the first years of the war, forces of the regency prevailed. In the wake of several anti-aristocratic uprisings, most notably that of the Zealots in Thessalonica, a majority of the cities in Thrace and Macedonia came under regency control. With assistance from Stefan Dušan of Serbia and Umur Beg of Aydin, Kantakouzenos successfully reversed these gains. By 1345, despite Dušan's defection to the opposition and the withdrawal of Umur, Kantakouzenos retained the upper hand through the assistance of Orhan, ruler of the Ottoman emirate. The June 1345 murder of megas doux Apokaukos, the regency's chief administrator, dealt the regency a severe blow. Formally crowned as emperor in Adrianople in 1346, Kantakouzenos entered Constantinople on 3 February 1347. By agreement, he was to rule for ten years as the senior emperor and regent for John V, until the boy came of age and ruled alongside him. Despite this apparent victory, subsequent resumption of the civil war forced John VI Kantakouzenos to abdicate and retire to become a monk in 1354.

The consequences of the prolonged conflict proved disastrous for the Empire, which had regained a measure of stability under Andronikos III. Seven years of warfare, the presence of marauding armies, social turmoil, and the advent of the Black Death devastated Byzantium and reduced it to a rump state. The conflict also allowed Dušan to conquer Albania, Epirus and most of Macedonia, where he established the Serbian Empire. The Bulgarian Empire also acquired territory north of the Evros river.