Milutin is credited with strongly resisting the efforts of Byzantine Emperor Michael VIII Palaiologos to impose Roman Catholicism on the Balkans after the Union of Lyons in 1274.

Peace was concluded in 1299 when Milutin kept the conquered lands as the dowry of Simonis, daughter of Emperor Andronikos II Palaiologos who became his fourth wife.

They regularly attacked Stefan Dragutin's Syrmian Kingdom, in Mačva, an area previously under the sovereignty of Elizabeth of Hungary.

Another campaign, this time organized by both Dragutin and Elizabeth, failed to conquer Darman and Kudelin's domains in 1285 and suffered another counter-raid by the brothers.

Responding to Dragutin's annexation of Braničevo the Bulgarian prince named Shishman that came to rule the semi-independent principality of Vidin around 1280, began to attack the Serbian domains to his west.

Disputes began between Milutin and his brother Stefan Dragutin after a peace treaty with the Byzantine Empire was signed in 1299.

[12] In order to gain an edge in his feud with Dragutin, Milutin sought support from the Papal States, even offering to convert himself and Serbs collectivly to Catholicism.

[14] The Battle of Gallipoli (1312) was fought by Serbian troops sent by Stefan Milutin to aid Byzantine Emperor Andronikos in the defense of his lands against the Turks.

After numerous attempts in subduing the Turks, the rapidly crumbling Byzantine Empire was forced to enlist the help of Serbia.

That was not acceptable for king Charles I of Hungary, who started to seek allies against Serbia, including those among Albanian nobles, who were also receiving support from Pope John XXII.

[17][18] Time of his reign was marked hostility to Catholicism, particularly in coastal regions, inhabited by religiously mixed population, that included Catholics and Eastern Orthodox Christians.

After his death a short civil war followed, after which the Serbian throne was ascended by his eldest son, Stefan Dečanski.

Stefan Milutin is mentioned in the Dante Alighieri's narrative poem Divine Comedy with the characteristics of counterfeiters due to the copying of Venetian money.