The museum is located in the centre of the city, in the palatial mansion at 4 Gavannaya Street. The mansion was built in 1876 by the project of Odessa architect Felix Gonsiorovskiy, for one of the major representatives of the industrial and commercial elite, Alexander Novikov. Novikov was the grandson of Odessa merchant, Ilya Novikov, owner of a cable factory that was founded in 1806.
The architecture of the two-storey mansion, as in previous works of Felix Gonsiorovskiy, is based on the style of the late Renaissance, with a variation of patterns and motifs drawn from the architectural heritage of Italy.
Until 1899, the mansion was known in Odessa as the "House of Novikov," and in the early 20th century it was acquired by the city government. In 1907, the house was leased to Odessa commercial collection.
After October 1917, the house often changed owners; it was used as a club, library, and a regional party courses. The basement and part of the ground floor rooms were used as a housing stock.
The first museum exposition was placed here in 1948. It was an exhibition of "Heroic Defense of Odessa", on the basis of which the Republican Museum of Odessa Defense formed subsequently.
On the 6th of May 1956 Odessa State Museum of Local History hospitably opened its doors to its first visitors. Documents, publications, objects of fine and applied arts, numismatic collections of XVII - XIX centuries, connected with the history of the city and region, and once were part of the collection of the Museum of the Odessa Society of History and Antiquities, Book Museum, Old Odessa Museum and some others, were an integral part of its funds.
In 1983, the museum was closed for capital repairs, which lasted for eleven long years. As a result, the forces of the Odessa art-restoration workshops palace interiors of the mansion were restored to its original form.
The museum's exposition includes about 120,000 exhibits and is considered one of the best in Ukraine.