The first written notes of Nyíregyháza date back in 1209, although it was called only Nyír ('birch'), after the Nyírseg, the greater region in which the city lies. A source from 1326 mentions that by then the city already had a church, hence the second part of the name, egyház (meaning 'church, cathedral' but literally 'one/singular house'). In the middle of the 15th century the town had cc. 400 inhabitants. In the 16th century, during the Turkish occupation of Hungary Nyíregyháza became deserted, and was resettled only in the 1630s – 1640s.
After the War of Independence led by Prince Francis Rákóczi II, the population of the town increased. Most of the new settlers were Slovaks from the area of Békéscsaba. In 1786 Nyíregyháza was granted the right to hold four market days a year, by this time the town was the biggest town of the county with 7,500 inhabitants. In the early 19th century Nyíregyháza was wealthy enough to become free from her feudal lords, the families Dessewffy and Károlyi. During these prosperous years the town got a new town hall, a hospital, several schools and a restaurant by the nearby lake Sóstó ("salty lake").
The inhabitants of the town took an active part in the revolution and war of independence in 1848-49, and after the suppression of the revolution several citizens were imprisoned, among them the mayor, Márton Hatzel.
In the second half of the 19th century Nyíregyháza became more and more urbanized and in 1876 the town became the county seat of Szabolcs county (which is now part of the larger integrated county Szabolcs-Szatmár-Bereg). In 1858 the railroad line reached Nyíregyháza, several new buildings were built, including a telegraph office, the main post office and the theater. In 1911 the construction of tramways was finished.
After the many trials and tribulations of World War I Nyíregyháza was under Romanian occupation for ten months. Between the two world wars the city
