The fall of the Serbian Empire was a decades-long process in the late 14th century. Following the death of the childless Emperor Stefan Uroš V in 1371, the Serbian Empire was left without an heir and the magnates, velikaši, obtained the rule of its provinces and districts (in so-called feudal fragmentation), continuing their offices as independent with titles such as gospodin, and despot, given to them during the Empire. This period is known as the dissolution or the beginning of the fall of the Serbian Empire.

Between 1365 and 1371, King Vukašin was the co-ruler of Emperor Uroš, ruling the southern half, thus the Empire may be viewed as a de facto diarchy. Before 1371, the nobility were either directly subordinate to Emperor Uroš or to Vukašin. Vukašin died in the Battle of Maritsa (1371) against the invading Ottoman Empire, and southern Serbian provinces became nominal Ottoman vassals. Four months later, Uroš died. The lords could not agree on the rightful ruler; they dismissed Prince Marko, the son of Vukašin, and conflicts started between the nobles within a year. An assembly was held in 1374 without any success since the nobles were unable to agree on whether Marko or Prince Lazar would head the Serbian confederation as the Serbian king and the state continued as before, fragmented and without central authority.

The period after the death of Uroš and Vukašin (1371–89) was marked by the rise and fall of Prince Lazar, and the power struggle of the minor provinces. Lazar ruled the most powerful Serbian principality, Moravian Serbia. The rule of Lazar ended with his death in the Battle of Kosovo in 1389, when Serbia stood up against invading Ottomans, an event that is deeply rooted in Serbdom. By 1395, most of the southern provinces had been conquered and annexed by the Ottomans, and the provinces of modern Central Serbia had accepted nominal Ottoman rule. Lazar was succeeded by his son, Stefan Lazarević, who ruled the rump Serbian Despotate, which finally fell to the Ottomans in 1459, thus marking the end of the medieval Serbian state.

Emperor Dušan's son and heir Stefan Uroš V (1356–71), though by this time twenty years old, was weak, and unable to take forceful action against his nobles' separatist tendencies, hence his sobriquet "the Weak", as opposed to his father Dušan's, "the Mighty".

Dušan's half-brother Simeon Uroš was expelled from Epirus and sought to obtain Serbia. He marched on Serbia in 1357 after he had himself proclaimed Tsar of the Greeks, Serbs, and Albanians at Kastoria in 1356. The forces of Stephen Uroš met the forces of Simeon near Scutari in Zeta and forced them to back down. Meanwhile, in the Serbian, Bulgarian and Byzantine borderlands of western Thrace, Matthew Kantakouzenos, the son of the Byzantine emperor John VI Kantakouzenos made war on the Serbs in 1356-57 but failed to capture Serres with his five-thousand Turks and was soon defeated in battle by Vojvoda Vojin and held for ransom. The ransom was paid by the Emperor John V Palaiologos and Matthew was allowed to retire to Morea. Now the lands that remained loyal to Uroš were most of Macedonia, including the land between the Struma and Mesta rivers and the Chalcidice peninsula. The lands that remained Serbian could be divided into three main parts: the western territories, including Zeta, the central Serbian lands of Uroš and the southern lands (including the eastern part of Macedonia with Serres as its capital).

The most powerful noble was Vojislav Vojinović who quarrelled with the Republic of Ragusa in the fall of 1358, when the Serbs and the Hungarians clashed along the Danube. The Hungarians penetrated deep into Serbian territory and the Serbian army retreated to avoid battle with the attackers. Vojislav waited until the Hungarians withdrew in 1359 then he attacked Ragusa. In 1365 Vukašin was proclaimed King of Serbia and co-ruler with Uroš, and Jovan Uglješa was made Despot in the Serbian Principality of Serres [bg].

There was a far more serious problem for Serbia — and the whole Balkans — than the internal squabbling of the Serbian nobles, and that was the advance of the Ottoman Turks in Europe. Followed by their penetration into Thrace, in 1354 they acquired Gallipoli on the European side of the Dardanelles. From there, they expanded into Thrace taking Demotika from the Byzantines in 1361 and Philippopolis from the Bulgarians in 1363 and finally in 1369 the major city of Adrianople. By 1370 Turks had occupied most of Thrace to the Rhodopes and the Balkan Mountains. As they reached the Rhodopes they collided with Jovan Uglješa who had extended his realm beyond the Mesta into this territory and the threat from them became increasingly serious.

On September 26, 1371, King Vukašin with his brother Despot Jovan Uglješa led the Serb Army against the advancing Ottoman Empire led by the beylerbey of Rumeli Lala Şâhin Paşa at the Battle of Maritsa. The offensive against the Turks was originally scheduled for early 1371 but was delayed perhaps because Uglješa had hoped that Bulgaria might also join the coalition. King Vukašin and his son Marko were in Scutari preparing for action against Nicholas Altomanovich when they were summoned east to join up with Uglješa and his army and then together they easily penetrated what was supposedly Turkish territory and reached Cernomen on the Maritsa River, where the Serbs did not bother to post sentries or have scouts as did the Turks. Furthermore, they did not keep their horses or their weapons in readiness and they allowed themselves to be surprised. The Ottomans won the battle, as they attacked the Serbian army while they rested. The bodies of the commanders were not found.