The first traces of settlement activity date from the 2nd-3rd centuries AD, when the Romans built the “Kaleto” fortress. In the times of the Ottoman invasion in the end of the 14th century most of the villages in the area were wiped out. The survivals sought for refuge in the less accessible vicinities. Mezdra itself existed in the Middle Ages by the name of Torbaritsa - a settlement and a fortress, which were also destroyed in 14th century.

The place remained uninhabited for a long time, hence the name “mezrata” - “an empty and deserted place”. It was not until the first half of the 19th century when herdsmen from the nearby villages settled at “Princhovets” locality, 2 km to the West from the present-day town, on the Kamenitsa River. Before the Liberation some 15-20 houses with “gray roofs covered with thin limestone slabs” existed (Felix Kanitz) with a total number of 68 residents. From 1878 on the population moved to the “Selishteto” locality, led by the mayor Danko Ivanov.

The first census of the population of Bulgaria, that took place on January the 1st 1881, reported 86 residents living in Mezdra. It was one of the three smallest villages in the then Vratsa county. Though in 1887 a bridge was built on the Iskar River, making possible the transfer of people and goods from Sofia and Orhanie (the present-day town of Botevgrad) to Vratsa, the village remained an insignificant one and in 1888 had 17 households and 76 residents. 1893 turned to be decisive for the development of Mezdra, for in that year the construction of the railroad between Sofia and Roman started. During four years hundreds of workers took part in the laying the rails, building tunnels, bridges and stations and repairing roads. The new railroad was inaugurated by the metropolitan bishop Constantine on February the 20th 1897. Count Ferdinand and Countess Maria Louisa, the Serbian king Alexander and the Prime-minister dr. Constantine Stoilov, which arrived by train from Sofia, attended the ceremony

The writers Ivan Vazov and Aleko Konstantinov were among the first tourists, eager visit this so far unknown part of Bulgaria. Vazov describes his journey that took place in the end of March 1897 in a short story entitled “Travel notes on the Sofia-Roman railroad”, published in the newspaper “Mir”. Aleko Konstantinov published his travel notes “Sofia-Mezdra-Vratsa” in “Zname” newspaper. Some years later Vassil Kanchov passed through Mezdra on his way to his home town Vratsa and mentioned that the village had become renowned for his station and the large distillery (“Sofia-Eliseyna-Zgorigrad-Vratsa-Mezdra”).
In the end of the 1920s only the name was what remained from the old village and everything else was renovated and keeping pace with the new century. Officially Mezdra was still a village, but no more cattle-sheds and sheep pens were to be seen, but new houses and civic buildings. And while in 1900 Mezdra had only 311 residents, in 1920 they already were 1015. From an architectural point of view the village looked more like a small, but modern town. Due to the presence of graduates of elite German higher educational institutions a West-European style was established in Mezdra and the nearby villages. Mezdra was proclaimed a town on August the 31st 1950 with decree no. 435.