The Epigraphic Museum was founded at its current location in 1885. The architect Patroclos Karantinos refurbished it with new spaces and gave the museum its present form in the 1950's.

Kyriakos Pittakis painstakingly gathered the inscriptions, which formed the first nucleus of the museum's collection, from different parts of Athens. These were supplemented by inscriptions from the collections of the Archaeological Society (Varvakeion) and finds from the Acropolis excavations. New examples from systematic excavations and surface finds, mainly from Attica but also from other parts of Greece, continued to enrich the museum's collection until approximately 1960 when new acquisitions, with the exception of a few donations and joining fragments from other museums (mostly the Ancient Agora), ceased for lack of space.

Vasileios Leonardos undertook the first inventory of the museum's collection at the end of the nineteenth and beginning of the twentieth centuries. Because this coincided with the publication of the academic series Inscriptiones Graecae, the inscriptions were classified and inventoried by subject matter, and displayed in that order. Markellos Mitsos followed more or less the same principal during the radical renovation of the display following World War II. Mitsos's work was completed by Constantina Delmouzou. The lobby and more recent rooms (9 and 11) were given an instructive and academic character, in accordance with contemporary museological principals, during their refurbishment in the 1990s. In an effort to modernize the permanent collection, the bilingual (Greek-English) labels were replaced by new and more informative texts.

In an adjacent to the museum building, a temporary exhibition gallery has been formed, There, the exhibition "Καττάδε έδοξε τοις Λακεδαιμονίοις. State documents from 5th cent. B.C. Sparta" has been organised in collaboration with the Greek Epigraphic Society, as well as the exhibition "Πολιτεύεσθαι τους Κείους κατά πόλεις. Disruption as a means of political control" in collaboration with the Center of Greek and Roman Antiquity of the National Research Foundation. Furthermore, painting exhibitions of modern Greek visual artists with subjects inspired by the Greek writing and ancient inscriptions have been organised.

In the same building, there is a conference room for the organisation of scientific meetings, lectures and the "Epigraphic Seminar" that takes place in collaboration with the Greek Epigraphic Society, the French Arcaeological School of Athens and the British School of Athens.