Before Hungarians founded Hungary a number of different tribes lived in the area. The town came into existence after some of the small villages of the area (Boldogasszonyfalva, Szentlászlófalva and Debreczun) merged. It experienced rapid development after the middle of the 13th century.
In 1361 Louis I of Hungary granted the citizens of Debrecen the right to choose the town's judge and council. This provided some opportunities for self-government for the town. By the early 16th century Debrecen was an important market town.
King Sigismund, Holy Roman Emperor, as part of a treaty with Serbian ruler Stefan Lazarević, gave him the opportunity to rule Debrecen in September 1411. A year after Lazarević's death in 1426, his role was taken over by his successor, Đurađ Branković. Between 1450 and 1507, it was a domain of the Hunyadi family.
During the Ottoman period, being close to the border and having no castle or city walls, Debrecen often found itself in difficult situations and the town was saved only by the diplomatic skills of its leaders. Sometimes the town was protected by the Ottoman empire, sometimes by the Catholic European rulers or by Francis II Rákóczi, prince of Transylvania. This led the town's citizens to be open-minded and Debrecen embraced the Protestant Reformation quite early, earning the moniker "Calvinist Rome". At this period the inhabitants of the town were mainly Hungarian Calvinists. Debrecen became sanjak between 1541 and 1693 and orderly bounded to eyalets of Budin (1541–1596), Eğri (1596–1660) and Varat (1660–1693) as "Debreçin".
In 1693 Leopold I, Holy Roman Emperor elevated Debrecen to free royal town status. In 1715, the Roman Catholic Church returned to Debrecen, and the town gave them a place to build a church, so the Piarist monks could build the St. Anna Cathedral. By this time the town was an important cultural, commercial and agricultural centre, and many future scholars and poets attended
