Emperor Uros (pr. OO-rosh) was forced to take the Serbian throne at the age of 18, following his father's unexpected death. Known in the epic tradition as Uros "the Weak", he was not capable of keeping his father's empire intact. The powerful landlords and magnates, enjoying their growing independence, were unwilling - or unable - to find guidance and cohesion in Dusan's heir. Dusan's half-brother Simeon (Sinisa) was the first to assert independence from the emperor in Epirus and Albania. His secessionist aspirations northward were checked in 1358, but centrifugal forces persisted elsewhere. Serbian nobility still loyal to the emperor considered themselves the masters of their territories and often styled themselves as his "allies and friends".

Regional lords, in fact, behaved like rulers on a small scale - they minted money and exacted tolls, depriving the emperor and central government of his rights and revenues. Many monastic estates were abandoned, and we are told that merchants setting out for Serbia frequently turned back. Emperor Uros was ultimately forced to divide his power with the most powerful among the Serbian noblemen - Vukasin Mrnjavcevic, the master of northern and eastern Macedonia - giving him the title of king and the rights of a co-ruler in 1365. While the fact that Uros was childless (eldest sons being the traditional junior rulers in the Nemanjic monarchy), coupled with political necessities, probably mandated the selection of a ruling colleague and heir apparent, 1365 in some sense marks a precedent and an end to the Nemanjic empire as traditionally understood until then. Nevertheless, during the latter part of Uros' reign, the core of the state was nominally still there, though truncated by the loss of southernmost Greek areas (most of Albania, Epirus, and Thessaly); it contained the central Serbian core under the direct rule of Uros, western nobles (Zeta and beyond), and the south-east areas (Macedonia and Serres), the latter two nominally loyal to the central government.

Lifetime fresco portraits - particularly the one in Psaca monastery near Kriva Palanka that shows Uros (ca. 1368, in the position of the senior ruler) and Vukasin, depict a handsome and stately young man, but chroniclers imply that his mental capacities in no way matched his physical appearance. He died suddenly in December of 1371, two months after the disastrous battle of Marica, which he did not participate in. Later tradition portrayed Vukasin as a conspirator directly responsible for his lord's death. This is historically unlikely, but the whole context - Uros being clearly the final legitimate member of the holy Nemanjic dynasty, coupled with the tragic disintegration of its fruits and objectively disloyal demeanor of some key subjects - was sufficient for the Church to have him understood as a tragic figure and martyr, and indeed have him subsequently canonized. His relics, having traveled - like those of so many other saints over the turbulent centuries - around many places, eventually quietly settled at Belgrade's main church (Saborna crkva) along with the earthly remains of several other Serbian dignitaries.