The earliest mention of a manuscript repository in Armenia was recorded in the writings of the fifth century historian Ghazar Parpetsi, who noted the existence of such a repository at the Etchmiadzin catholicosate in Vagharshapat, where Greek and Armenian language texts were kept. Sources remain silent on the fate of the Etchmiadzin matenadaran until the 15th century, when the catholicosate returned from Sis in Cilicia. Manuscript repositories existed at major monasteries in medieval Armenia, such as at Haghpat (Haghpat matenadaran), Sanahin, Saghmosavank, Tatev, Geghard, Kecharis, Hromkla, and Bardzraberd.
In some cases, monastic complexes have separate structures as manuscript repositories. Sometimes manuscripts would be transferred to caves to avoid destruction by foreign invaders. Thousands of manuscripts in Armenia were destroyed over the course of the tenth to fifteenth centuries during the Turkic and Mongol invasions. According to the medieval Armenian historian Stepanos Orbelian, the Seljuk Turks were responsible for the burning of over 10,000 Armenian manuscripts in Baghaberd in 1170.
As a result of Armenia being a constant battleground between two major powers, the Matenadaran in Etchmiadzin was pillaged several times, the last of which took place in 1804, during the Russo-Persian War. Eastern Armenia’s annexation by the Russian Empire in the early 19th century provided a more stable climate for the preservation of the remaining manuscripts. Whereas in 1828 the curators of the Matenadaran catalogued a collection of only 1,809 manuscripts, in 1863 the collection had increased to 2,340 manuscripts, and in 1892 to 3,338 manuscripts. Prior to World War I, in 1914, the collected had reached 4,660 manuscripts.The collection was sent to Moscow for safekeeping since Etchmiadzin was close to the war zone.
Thousands of Armenian manuscripts were destroyed during the genocide in the Ottoman Empire.
On December 17, 1920, just two weeks after the demise of the First Republic of Armenia and Sovietization of Armenia, the new Bolshevik government of Armenia issued a decree nationalizing all cultural and educational institutions in Armenia. The issue, signed by Minister of Education Ashot Hovhannisyan, declared the manuscript repository of Etchmiadzin the «property of the working peoples of Armenia.» It was put under the supervision of Levon Lisitsian, an art historian and the newly appointed commissar of all cultural and educational institutions of Etchmiadzin. In March 1922 the manuscripts from Etchmiadzin that had been sent to Moscow during World War I were ordered to be returned to Armenia by Alexander Miasnikian. 1,730 manuscripts were added to the original 4,660 manuscripts held at Etchmiadzin once they returned to Armenia.
In 1939 the entire collection of manuscripts of Etchmiadzin were transferred to the State Public Library in Yerevan (what later became the National Library of Armenia) by the decision of the Soviet Armenian government.
In the same year there were 9,382 cataloged manuscripts at the Matenadaran. On March 3, 1959, the Council of Ministers of Soviet Armenian officially established the Matenadaran as an «institute of scientific research with special departments of scientific preservation, study, translation and publication of manuscripts» in a new building. It was named after Mesrop Mashtots, the creator of the Armenian alphabet, in 1962.