With a history going back nearly 3,000 years, Nusaybin was ruled and settled by various groups. First mentioned as an Aramean settlement Naşibīna in 901 BCE, it was captured by Assyria in 896 BCE. In the 4th and 5th centuries CE it was one of the great centers of Syriac scholarship, along with nearby Edessa.
First mentioned in 901 BCE, Naşibīna was an Aramaean kingdom captured by the Assyrian king Adad-Nirari II in 896. By 852 BCE, Naṣibina had been fully annexed to the Neo-Assyrian Empire and appeared in the Assyrian Eponym List as the seat of an Assyrian provincial governor named Shamash-Abua. It remained part of the Assyrian Empire until its collapse in 608 BCE.
It was under Babylonian control until 536 BCE, when it fell to the Achaemenid Persians, and remained so until taken by Alexander the Great in 332 BCE. The Seleucids refounded the city as Antiochia Mygdonia (Greek: Ἀντιόχεια τῆς Μυγδονίας), mentioned for the first time in Polybius' description of the march of Antiochus III the Great against Molon (Polybius, V, 51). Greek historian Plutarch suggested that the city was populated by Spartan descendants. Around the 1st century CE, Nisibis (נציבין, Netzivin) was the home of Judah ben Bethera, who founded a famous yeshiva there.
Like many other cities in the marches where Roman and Parthian powers confronted one another, Nisibis was often taken and retaken: it was captured by Lucullus after a long siege from the brother of Tigranes (Dio Cassius, XXXVI, 6-7); and captured again by Trajan in 115 CE, for which he gained the name of Parthicus (ibid., LXVIII, 23), then lost and regained against the Jews during the Kitos War. Lost in 194, it was again conquered by Septimius Severus, who made it his headquarters and re-established a colony there (ibid., LXXV, 23). The last battle between Rome and Parthia was fought in the vicinity of the city in 217. With the fresh energy of the new Sassanid dynasty, Shapur I conquered Nisibis, was driven out, and returned in the 260s. In 298, by a treaty with Narseh, the province of Nisibis was acquired by the Roman Empire.
Nisibis (Syriac: ܢܨܝܒܝܢ, Nṣibin, later Syriac ܨܘܒܐ, Ṣōbā) had an Assyrian 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 St Jacob or James of Nisibis, Babu's successor, was its bishop. Nisibis was the home of Ephrem the Syrian, who remained until its surrender to the Sassanid Persians by Roman Emperor Jovian in 363.