Although no definitive information is available about the time when the city of Mardin was first established, it can be said that the foundation of  city dates back to the time of the Subarid according to the antique history of the Near East.
According to the results of the excavations conducted by German Archaeologist Baron Marvan Oppenheim in 1911-12, the Subarid lived in Mesopotomaia around 4500-3500 BC. This result is based upon tiles found in-among layers that belong to the Sumerians and Babylonians.
In one recent archaeological excavation  carried out from1982 to 1991 at Gırnavaz it was found that Gırnavaz was a continuous settlement from 4000 BC to the 7th century AD. The late Uruk era which constitutes the bottom culture layer in Gırnavaz dates back to 4000 BC. The architectural layers of Er Dynasty era just above the bottom layer was investigated in relation to burial traditions and practices. According to findings obtained in this second layer from the bottom, dead people are placed in graves with their knees close to abdomen, a light fire is set to clean their souls and cut off their remaining earthly relations, and finally graves are closed. Many personal items such as metal weapons, ornaments, ceramics and bullae were found in these graves.

In 2850 BC King Lugarzergis of Sumer occupied Mardin during his military campaign that extended to the Mediterranean coast.
Sumerians who were at a rather high level in city planning, irrigation and agriculture lost their power mainly for the vastness of the area they had to control and so they had to leave Mardin to Akads after 30 years (2820 BC). Around 2500 BC Akads had a treaty with Sumerians, which led to the establishment of an Akad-Sumer State.
In his book “Turkey in Antique Times” historian Prof. Ekrem Memiş writes,  “according to the documents of Semitic Akads, a people called “Hurris” were living in Southeastern Anatolia, Mardin being the center, and area between Musul and Kerkük towards the end of 3000 BC.”
Mardin became an Elam city around 2230 BC. Hammurabi from Amuri Dynasty annexed Sumerian land and established the Babylonian State , then annexed Mardin too (2200-1925 BC).
The Hittites invaded Mardin in 1925 BC and left it a year later. Then Midils of Arian origin coming from Persia occupied Mardin and its territory. After dominating the area for 500 years these people became the subject of the rulers of Egypt. Upon the outbreak of a Midil civil war in 1367 BC, Assyrian King Asurobalit occupied Mardin.
Around 1190 BC Mardin was in the hands of some Arian people coming down from Anatolia. 60 years after King Tıplatpalasır I defeated these people and recaptured Mardin together with Sincar and Nusaybin.
In 1060 BC, during the reign of Asurnasırbal I, the Hittites joined their forces and defeated Assyrians around Gılgames. But Mardin again came under the influence of the Assyrians after they recovered their power. Ruled by the Assyrians until 800 BC, Mardin was then occupied by Urartu Kingdom and ruled by this Kingdom for 50 years corresponding mostly to the region of King Mimes.
Following the rules of Sityanis and Midils around 600 BC, Alexander the Great turns his route to Mardin in 335 BC to move ahead to Persia after his conquest of Egypt. After his death in Babil in May 28, 323 BC his empire was divided up among his military commanders and Mardin fell to the share of General Selevkos who was also known as “Nikanır” (311 BC).
In 131 BC Mardin and its surrounding area was annexed by the Kingdom of Urfa (Abgars). In 249 AD, Roman ruler Filibos led a rebellion and drove King Abgar IX out of Mardin. Uralyonos became the governor of the city. Mardin, as a settlement administratively attached to Urfa came under Roman Rule. Meanwhile Dakiyos conquers the Persian land in 250 AD and restores the city of Nusaybin. In 330, a king named Şad Buhari, who worships fire and sun, starts to stay in Mardin castle for his illness. Recovering during his staying there, Şad Buhari builds a palace for himself and lives in Mardin for 12 more years. Then he brings many soldiers and civilians from his native land Persia to settle in. These people introduce many improvements to the city until 442 AD but a plague breaks out and devastates the city shortly afterwards. After about 100 years a Roman Commander named Ursianos rebuilds the city in 47 years and makes it inhabitable again.In this period Dara was reconstructed. The Byzantine could rule the city until 640 when İlyas bin Ganem, one of the military commanders of Caliph Ömer occupied the city. Then the area was ruled first by the Emevi dynasty starting from 692 and then by the Abbasid starting in 824 with the reign of Caliph Memnun.

The Hamdani rule in the area from 885 to 978 led to the capture of the city in 895. These were the people who reconstructed and fortified the castle, which still stands in our day. However, the Hamdani rule was to give its place to Mervani in 990. Their contribution was important in the sense that they built many bazaars and mosques and made Mardin a trade center on the Silk Route.
The Mervani gradually lost power under the pressure of Turkish raids starting after Malazgirt Battle of 1071.They were finally defeated in Nusaybin by Seljuk Turks in 1089.
İl Gazi Bey of Artuklu Dynasty captured the city and made it the capital of its domain in 1105. İl Gazi Bey made a great fame for his capture of Aleppo and fierce resistance against the Crusades. He captured Silvan following his victory over Prince Roger of Antioch. After his death his sons and close relatives expanded the domain to Diyarbakır and Harput and added to their success by defeating Crusades, Franks, Count of Urfa, Count of Bilecik and Bodven, the King of Jerusalem. The Kingdom of Artuklu lasted for 304 years during which many new mosques, madrassa, bathes and caravansaries were built.
In 1393 Tamerlane surrounded the city but was unsuccessful in capturing it.   Tamerlane gathers a large army and again attempts to capture the city in 1395. The city defended itself severely enough to prove these attempts futile and route Tamerlane who then had the most powerful army in the world.
Relief from the threat of Tamerlane encourages the Artuklu to further develop the city, but this intention faces a new threat coming from the Kingdom of Karakoyunlu. After two years under siege the defenders of Mardin make a treaty with Karakoyunlu and surrender. The city remains under Karakoyunlu rule for 61 years. But this period was rather turbulent. Tribes in the area frequently rose up against the rule. The Akkoyunlu Kingdom defeats Karakoyunlu in 1462 and captures the city. During the Akkoyunlu rule, Kasım Bey, a military commander posted to the city starts to restore the city once devastated by the attacks of Tamerlane. Kasım Paşa Medresse is one of the buildings of his rule which survived to our times.
In the early 16th century Şah İsmail of Iran brings Akkoyunlu under his yoke and comes to the fore with his powerful Shiite Empire. Şah İsmail was so ruthless against those who resisted him that the defenders of Mardin gave the keys of the city to İsmail in order to protect people and prevent bloodshed.
The city of Mardin came definitely under Ottoman Rule during the Egyptian campaign of Yavuz Sultan Selim. Bıyıklı Mehmet Paşa, Governor of Diyarbakır (Amid) and İdris-I Bitlisi, a local Kurdish leader tried to capture the city for 9 months starting in 1516 and took it, though after fierce fighting, with the support of other Kurdish tribes in the area. Finally on 7 April 1517 the city was captured and news about this success made Selim pleased,who was the first Ottoman Caliph   in Egypt. As a part of Ottoman territory, Mardin was attached to Diyarbakır. In 1518, the “Sanjak” of Mardin consisted of the central town, Savur and Nusaybin. In this Sanjak, there were both settled and nomadic people. The settled people of the area included Jews, Christians (Armenians, Suryani and Keldani), Moslems and some Şemsi (worshippers of sun).