It was founded in 1701 and was granted town status in 1809. Novozybkov was a major hemp supplier in the 18th and 19th centuries, particularly for the production of ropes for the Imperial Russian Navy. Following the Crimean War, the demand for hemp fell, and cultivation stopped altogether at the beginning of the 20th century.
On April 26, 1986, Novozybkovsky District and the neighbouring Krasnogorsky District were contaminated with radioactive fallout from the Chernobyl disaster. Today, these two areas remain the most contaminated in the Russian Federation as to the total contaminated area and the intensity of contamination (curies per km²). The area not suitable for human habitation (more than 40 curies per km²) starts at 1 km west of Novozybkov city limits.
Within the framework of administrative divisions, Novozybkov serves as the administrative center of Novozybkovsky District, even though it is not a part of it. As an administrative division, it is incorporated separately as Novozybkovsky Urban Administrative Okrug—an administrative unit with the status equal to that of the districts. As a municipal division, Novozybkovsky Urban Administrative Okrug is incorporated as Novozybkov Urban Okrug.