For more than two centuries the fate of Sirmium was unknown. At the end of the 8th century, Sirmium belonged to the Frankish State. The historical role of Sirmium increased again in the 9th century, when it was part of Bulgarian Empire. Pope Adrian II gave St. Methodius the title of Archbishop of Sirmium. After having adopted Christianity, the Bulgarians restored in Sirmium the Christian Episcopate, having in mind old Christian traditions and the reputation this city had in the ancient world.
In the 11th century, Sirmium was a residence of Sermon, a duke of Syrmia, who was a vassal of the Bulgarian/Macedonian emperor Samuil. After 1018, the city was again included into the Byzantine Empire, and since the end of the 11th century, Sirmium was a subject of a dispute between the Byzantine Empire and the Kingdom of Hungary, until 1180 when the Byzantine Empire gave up Sirmium, surrendering it to the Kingdom of Hungary. In the 11th century, an Byzantine province named Theme of Sirmium had its capital in this city.
For a while, about 1451, the city was in possession of the Serbian despot Brankovic. In 1521 the city came into Ottoman hands and it remained under the Ottoman rule for almost two centuries. According to Ottoman traveler Evliya Celebi, Mitrovica had been conquered by the Bosnian sanjak bey Husrev-bey. She was renamed as "Dimitrofça".
According to the 1545/1548 data, the city was mainly populated by ethnic Serbs, while the name of the mayor of the city was Dimitar. Since the middle of the 16th century, the city was mostly populated with Muslims. According to the 1566/69 data, the population of the city was composed of 592 Muslim and 30 Christian houses, while according to the 1572 data, it was composed of 598 Muslim and 18 Christian houses. According to the 1573 data, the city had 17 mosques and no Christian church. During the Ottoman rule, Sremska Mitrovica was the largest settlement in Syrmia, and was the administrative center of the Ottoman Sanjak of Syrmia.
With the establishment of the Habsburg administration in 1718, the Muslim population fled from the city and was replaced with Serbian, Croatian, and German settlers. According to the 1765 data, the population of the city numbered 809 people, of whom 514 were Serbs and 290 Catholics. Sremska Mitrovica was part of the Habsburg Military Frontier (Slavonian Krajina). In 1848/1849, it was part of the Serbian Voivodship , a Serb autonomous region within Austrian Empire, but in 1849, it was returned under administration of the Military Frontier.
With the abolition of the Slavonian Military Frontier in 1881, Sremska Mitrovica was included into Syrmia County, which was part of the Kingdom of Croatia-Slavonia and Kingdom of Hungary within Austria-Hungary. According to the 1910 census, the population of the city numbered 12,909 people, of which 4,878 spoke Serbian language, 3,915 Croatian, and 2,341 German. The municipal area of the city (which did not included the city itself) had 32,012 inhabitants, of which 27,022 spoke Serbian, 2,324 German, and 1,071 Croatian.