Argentine painter and art critic Eduardo Schiaffino, was the first director of the museum, which opened on 25 December 1895, in a building on Florida Street that today houses the Galerías Pacífico shopping mall.

Following the demolition of the pavilion in 1932, as part of the remodeling of Plaza San Martín, the museum was transferred to its present location in 1943, a building originally constructed in 1870 as a drainage pumping station and adapted to its current use by architect Alejandro Bustillo.

The museum commissioned architect Mario Roberto Álvarez to design a branch in the Patagonian region city of Neuquén.

The first floor's eight exhibit halls contain a collection of paintings by some of the most important 20th-century Argentine painters, including Antonio Berni, Ernesto de la Cárcova, Benito Quinquela Martín, Eduardo Sívori, Sarah Grilo, Alfredo Guttero, Raquel Forner, Xul Solar, Marcelo Pombo and Lino Enea Spilimbergo.

The second floor's two halls, completed in 1984, hold an exhibition of photographs and two sculpture terraces, as well as most of the institution's administrative and technical departments.