The museum was founded in 1891 under Sultan Abdülhamid II. by the painter and archaeologist Osman Hamdi Bey as Müzesi Humayun ("Museum of the Empire") as the central archaeological museum of the Ottoman Empire.
The architect Alexandre Vallaury built the building in neoclassical style (construction began in 1881). The collection part of the museum with art from Istanbul goes back in part to a cataloguing and collection project initiated by the then museum director Halil Edhem Eldem, which was carried out from January to the beginning of November 1918 with the collaboration of Friedrich Schrader and several Turkish art historians and building experts of the time, and which was intended to save and preserve Istanbul monuments and archaeological artefacts threatened by the effects of war and vandalism. As a photographer, the then owner of the photo studio Sebah and Joaillier, Hagop Iskender, belonged to the team.
The museum was awarded the Museum Prize of the Council of Europe in 1991.

The pieces of the museum come from the territory of the entire Ottoman Empire, today they are enriched by finds from Istanbul and its surroundings. The building has two floors. On the ground floor there are 20 exhibition rooms, on the upper floor there are 16 other rooms with smaller objects and sculptures from the Middle Ages and modern times. A new six-storey outbuilding is located southeast of the main building.---- Probably the best known individual object in the museum is the so-called Alexander sarcophagus from the 4th century BC, which was excavated in 1887 by the museum founder Osman Hamdi Bey in Sidon (Lebanon).

Other important objects are:
in hall 3: Sidamara sarcophagus (3rd century), discovered 1950 in Konya
in Room 10: Phoenician inscriptions from Sidon and man-made sarcophagi
in room 13: Lioness (4th century BC) from the Mausoleum of Halicarnassus
in hall 18: Colossal statue of Zeus
on the upper floor: bronzeware from Cyprus, Greek vases and coins. Among other things objects from Troy (for example drinking cups with a horizontal and a vertical handle).
the head of the snake column of the Hippodrome in the center of Istanbul.