The University's Honour School of Natural Science started in 1850, but the facilities for teaching were scattered around the city of Oxford in the various colleges. The University's collection of anatomical and natural history specimens were similarly spread around the city.
Regius Professor of Medicine, Sir Henry Acland, initiated the construction of the museum between 1855 and 1860, to bring together all the aspects of science around a central display area. In 1858, Acland gave a lecture on the museum, setting forth the reason for the building's construction. He viewed that the University had been one-sided in the forms of study it offered—chiefly theology, philosophy, the classics and history—and that the opportunity should be offered to learn of the natural world and obtain the "knowledge of the great material design of which the Supreme Master-Worker has made us a constituent part". This idea, of Nature as the Second Book of God, was common in the 19th century.
The construction of the building was accomplished through money earned from the sale of Bibles. Several departments moved within the building—astronomy, geometry, experimental physics, mineralogy, chemistry, geology, zoology, anatomy, physiology and medicine. As the departments grew in size over the years, they moved to new locations along South Parks Road, which remains the home of the University's science departments.
The last department to leave the building was the entomology department, which moved into the zoology building in 1978. However, there is still a working entomology laboratory on the first floor of the museum building.
Between 1885 and 1886 a new building to the east of the museum was constructed to house the ethnological collections of General Augustus Pitt Rivers—the Pitt Rivers Museum. In 19th-century thinking, it was very important to separate objects made by the hand of God (natural history) from objects made by the hand of man (anthropology).
The largest portion of the museum's collections consist of the natural history specimens from the Ashmolean Museum, including the specimens collected by John Tradescant the elder and his son of the same name, William Burchell and geologist William Buckland. The
Christ Church Museum donated its osteological and physiological specimens, many of which were collected by Acland.