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Colonel John Monroe, the then British Resident in the Kingdom of Travancore offered his unreserved support for the initiative. The queen of Travancore granted 16 acres (65,000 m2) of tax-free land, Rs.20,000 and the necessary timber for the construction of the Seminary. The work started in 1813 and the building was completed and classes began on March 1815.
The beginning of the Seminary synchronized with the arrival of Church Missionary Society (C.M.S) Missionaries to Kerala. For some years the relationship between the missionaries and the Church was one of cordial co-operation. The missionaries were allowed to teach English and biblical languages in the Seminary.
After a time the relationship of the Church with the later missionaries became strained as they interfered in the doctrinal matters of the Church leading eventually to disputes and litigation.. Soon after some time it became the residence and headquarters of the Malankara Metropolitan, the chief Metropolitan of the Malankara Church, accountable to the Patriarch of Antioch. The academic importance of the Seminary suffered when it became the centre of church administration. Nevertheless, it continued the programme of training ordinands. Eminent Malpans (recognized teachers of theology and liturgy) rendered service to the institution. Some of the distinguished teachers include St. Gregorios of Parumala( Gheevarghese Mor Gregorios), Dionysius of Vattasseril(Gheevarghese Mar Dionysius), Konat Mathan Corepiscopa, Skaria Cheriamadam, Skaria Elavinamannil, Alexander Mattakkal, Augen Mar Timotheos (later Catholicos Augen I), Mathews Mar Athanasios (later Catholicos Mathews I), Philipose Mar Theophilus and Paulos Mar Gregorios.
In 1942 the Seminary entered its modern period. A systematised course of studies was introduced. A new generation of qualified professors of theology and biblical studies took responsibility for running the Seminary. Classes and students' residence were moved to the new buildings in the campus of the M.D. Seminary at Kottayam. When the Catholicos moved his residence from the Old Seminary to the present Devalokam, theological education was once again brought back to the "Old Syrian Seminary ". In 1964 the Seminary became affiliated to the Serampore University for its B.D. degree course. 1965, the 150th year of its founding, was celebrated on a grand scale in the presence of ecclesiastical dignitaries and church leaders from abroad. The foundation stone of the new building was laid by Vasken I, Supreme Catholicos of the Armenian Apostolic Church of Etchmiadzin on 23 December 1963 during his historic visit to the Indian Orthodox Church. The generous contribution from the member churches of the World Council of Churches together with a matching contribution from the Malankara Orthodox Church members, made it possible to complete the building in a short period. Justinian, the Patriarch of Romania, declared open the new building on 7 January 1969, during his visit to the Malankara Orthodox Church. Other eminent visitors to the Seminary include Emperor Haili Selassie of Ethiopia, Patriarch Pimen of Moscow and All Russia, Patriarch Ilia of Georgia and the Ecumenical Patriarch Bartholomew I.
The M.D. Syrian Orthodox Seminary, in a unique ecumenical collaboration with the Marthoma Seminary and the C.S.I Seminary, Trivandrum, runs the prestigious Master's and Doctoral programmes under the banner of the Federated Faculty for Research in Religion and Culture.