[1] In 1876 the design for the first section was completed by George Curtis Walker,[3] under the direction of Queensland Colonial Architect FDG Stanley, and a construction contract for £10,701 was let to W. Macfarlane.

The building was erected as stage one of a complex which was to incorporate two flanking wings housing the main staircases, and an arcade and colonnade fronting the river.

[1][4][5] The choice of a classical style of architecture, modelled on 16th century Italian buildings and its central location close to the city's southern entrance, reflected the museum's importance in the scientific and cultural life of Brisbane.

The additions, designed by government architects WG Thain, P Prystupa, U Stukoff, AJ Wheeler, D Davies and H de Jong, included an exhibition hall on the western side and reading rooms on the river elevation.

[1][9] From 1964 to 1965 the original building underwent a major renovation, including the addition of a concrete frame structure, new floors, a mezzanine and air conditioning and the removal of the skylight, at a cost of over £227,000.

The facade is designed using classical elements, with a rusticated base and double-height columns rising from the piano nobile to support an entablature.

The centre of the facade is marked by an aedicular containing an arched doorway, at ground level (the original entrance, now blocked in) and a small pediment above in the entablature.

The western wall is decorated with Lindsay Edward's large glass mosaic mural, 20.7 by 4.4 metres (68 by 14 ft), the design suggesting "primitive organic forms indicative of growth and development".

[7] To the south the extension was designed as a series of concrete fin walls providing views of the river, private work areas and shade from the sun.