It is the ancient Mesopotamian city, which Alexander's successors refounded as Antiochia Mygdonia (Αντιόχεια της Μυγδονίας) and is mentioned for the first time in Polybius' description of the march of Antiochus I against the Molon (Polybius, V, 51). Greek historian Plutarch suggested that the city was populated by Spartan descendants. The Syriac name for the town is Soba.
The Roman historian of the 4th century Ammianus Marcellinus gained his first practical experience of warfare as a young man under the governor at Nisibis, Ursicinus. From 360 to 5th century, Nisibis was the camp of Legio I Parthica. Because of its strategic importance on the Persian border Nisibis was heavily fortified. Ammianus lovingly calls Nisibis the "impregnable city" (urbs inexpugnabilis) and "bulwark of the provinces" (murus provinciarum).
In 363 Nisibis was ceded back to the Persians after the defeat of Julian. At that time the population of the town was forced by the Roman authorities to leave Nisibis and move to Amida. The townspeople tried to persuade Emperor Jovian that they were ready to defend their home against the Persians, but Iovianus allowed them only three days for the evacuation. Historian Ammianus Marcellinus was again an eyewitness of this sorrowful event. He condemns Emperor Jovian for giving up the fortified town without a fight. Marcellinus' point-of-view is certainly in line with contemporary Roman public opinion.
Nisibis had a Christian bishop from 300, founded by Babu (died 309). War was begun again by Shapur II in 337, who besieged the city in 338, 346 and 350, when James, Babu's successor, was its bishop. Nisibis was the home of Ephrem the Syrian, who remained until its surrender to the Persians by Jovian in 363.
Later, the bishop of Nisibis was the ecclesiastic metropolitan of the Province of Beit-Arbaye. In 410 it had six suffragan sees and as early as the middle of the 5th century was the most important episcopal see of the Persian Church after Seleucia-Ctesiphon, and many of its Nestorian or Jacobite bishops were renowned for their writings: Barsumas, Osee, Narses, Jesusyab, Ebed-Jesus.
The first theological School of Nisibis, founded at the introduction of Christianity into the city, was closed when the province was ceded to the Persians. Ephrem the Syrian, a poet, commentator, preacher and defender of orthodoxy, joined the general exodus of Christians and reestablished the school on more securely Roman soil at Edessa. In the 5th century the school became a center of Nestorian Christianity, and was closed down by Archbishop Cyrus in 489; the expelled masters and pupils withdrew once more to Nisibis, under the care of Barsumas, who had been trained at Edessa, under the patronage of Narses, who established the statutes of the new school. Those which have been discovered and published belong to Osee, the successor of Barsumas in the See of Nisibis, and bear the date 496; they must be substantially the same as those of 489. In 590 they were again modified. The monastery school was under a superior called Rabban ("master"), a title also given to the instructors. The administration was confided to a majordomo, who was steward, prefect of discipline, and librarian, but under the supervision of a council. Unlike the Jacobite schools, devoted chiefly to profane studies, the school of Nisibis was above all a school of theology. The two chief masters were the instructors in reading and in the interpretation of Holy Scripture, explained chiefly with the aid of Theodore of Mopsuestia. The free course of studies lasted three years, the students providing for their own support. During their sojourn at the university, masters and students led a monastic life under somewhat special conditions. The school had a tribunal and enjoyed the right of acquiring all sorts of property. Its rich library possessed a most beautiful collection of Nestorian works; from its remains Ebed-Jesus, Bishop of Nisibis in the 14th century, composed his celebrated catalogue of ecclesiastical writers. The disorders and dissensions, which arose in the sixth century in the school of Nisibis, favoured the development of its rivals, especially that of Seleucia; however, it did not really begin to decline until after the foundation of the School of Baghdad (832). Among its literary celebrities mention should be made of its founder Narses; Abraham, his nephew and successor; Abraham of Kashgar, the restorer of monastic life; John; Babai the Elder.
Modern Nusaybin remains the site of two titular sees in the Roman Catholic Church, Nisibenus Chaldaeorum, and Nisibenus; the first seat is held by Jacques Ishaq, titular Archbishop, the second has been vacant since 1968.
Nusaybın made headlines in 2006 when villagers near Kuru (Xirabêbaba) uncovered a mass grave, suspected of belonging to Ottoman Armenians and Syriacs. Swedish historian David Gaunt visited the site in order to investigate its origins, but left after finding evidence of tampering. Gaunt, who has studied 150 massacres carried out in the summer of 1915 in Mardin, said that the Committee of Union and Progress's governor for Mardin, Halil Edip, had likely ordered the massacre on 14 June 1915, leaving 150 ethnic Armenians and 120 ethnic Assyrians dead. The settlement was then known as Dara (now Oğuz). Gaunt added that the death squad, named El-Hamşin (meaning "fifty men"), was headed by officer Refik Nizamettin Kaddur. The president of the Turkish Historical Society, Yusuf Halaçoğlu, said that the remains dated back to Roman times.
Özgür Gündem says that the military and police have pressured the media not to report the discovery.