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Ia telah diketahui bahawa John Radcliffe, doktor kepada William III dan Mary II dari England, berniat untuk membina sebuah perpustakaan di Oxford lebih kurang dua tahun sebelum kematiannya pada 1714. Ia difikirkan bahawa bangunan baru akan menjadi suatu extension westwards of the Selden End of the Bodleian Library. Francis Atterbury, Dean of Christ Church memikirkan sebuah bilik 90 kaki akan dibina di tanah Exeter College, dan bahawa tingkat bawah akan menjadi perpustakaan untuk Exeter College dan Perpustakaan Radcliffe di tingkat atas. Sebarang rancangan sudah tentu disediakan, oleh Nicholas Hawksmoor (empat belas 'Designs of Printing and Town Houses of Oxford by Mr. Hawksmoor' adalah di kalangan lukisan yang diberikan untuk jualan selepas kematian Hawksmoor), rancangan itu kini berada di Muzium Ashmolean. Wasiat Radcliffe, sungguhpun, dibukti pada 8 Disember 1714, jelas menunjuk niatnya bahawa perpustakaan akan dibina di tempat ia kini menduduki, mengatakan:

Dan akan itu para wasi saya membayar empat puluh ribu pound dalam jangka sepuluh tahun, dengan bayaran tahunan empat ribu pound, bayarang pertama oleh itu bermula dan dilakukan selepas kematian dua adik-beradik perempuan yang tersebut untuk pembinaan sebuah perpustakaan di Oxford dan membeli rumah rumah-rumah [sic] di antara St Maries dan scholes di Catstreet di mana saya bertujuan Perpustakaan dibina, dan apabila Perpustakaan tersebut dibina saya memberi seratus dan lima puluh pound untuk Perpustakaan sama.

Sebilangan rumah-rumah tenement houses menghadap Catte Street, dibina right up to the Schools, some gardens, Brasenose College outbuildings and Black Hall occupied the site required for the library. A number of colleges became involved in the development of the site. An added problem was that Brasenose required an equal amount of land fronting High Street in return for the land they were being asked to give up. As a consequence, the Trustees had to negotiate with the owners and the tenants of the houses. An Act of Parliament was passed in 1720 that enabled any corporations within the University to sell ground for building a library. The negotiations dealing with Catte Street took over twenty years.

The choice of architect had been considered as early as 1720 - Christopher Wren, John Vanbrugh, Thomas Archer, John James, Nicholas Hawksmoor, and James Gibbs were considered. In 1734 Hawksmoor and Gibbs were invited to submit plans. Hawksmoor made a wooden model of his design which is in the Bodleian. Gibbs was eventually chosen for the building.

On 17 May 1737, the foundation stone was laid. The progress of the building and the craftsmen employed is detailed both in the Minute Books of the Trustees and the Building Book, which supplement information given by Gibbs in his Bibliotheca Radcliviana. An extract states:Mr. William Townsend of Oxford, and Mr. William Smith of Warwick, were employed to be masons; Mr. John Philipps to be the carpenter and joiner; Mr. George Devall to be plumber; Mr. Townsend junior to be stone carver; Mr. Linel of Long-acre, London, to be carver in wood; Mr. Artari, an Italian, to be their plaisterer in the fret work way; Mr. Michael Rysbrack to be sculptor, to cut the Doctor's figure in marble; and Mr. Blockley to be locksmith.

Francis Smith, the father of William, was chosen as one of the masons, but died in 1738 and was succeeded by his son near the beginning of building. In 1739, John Townesend also succeeded his father on the latter's death.

The building was completed in 1748, and a librarian appointed, as was a porter. The opening ceremony took place on 13 April 1749 and soon known as 'the Physic Library'. Despite its name, its acquisitions were varied for the first sixty years, but from 1811 its intake was confined to works of a scientific nature. During the first half of the 19th century the collections included coins, marbles, candelabra, busts, plaster casts, and statues. These collections have since been moved to more specifically appropriate sites. Between 1909 and 1912 an underground book store of two floors was constructed beneath the north lawn of the library with a tunnel connecting it with the Bodleian, invisibly linking the two library buildings, something envisaged by Henry Acland in 1861.

After the Radcliffe Science Library moved into another building, the Radcliffe Camera became home to additional reading rooms of the Bodleian Library. The freehold of the building and adjoining land was transferred from the Radcliffe Trustees to the University in 1927. The interior of the upper reading-room houses a six foot marble statue of John Radcliffe, carved by John Michael Rysbrack. It now holds books from the English, history, and theology collections, mostly secondary sources found on Undergraduate and Graduate reading lists. There is space for around 600,000 books in rooms beneath Radcliffe Square.

Contemporaries found great irony in the fact that the iconoclast Radcliffe, who scorned book-learning, should bequeath a substantial sum for the founding of the Radcliffe Library. Sir Samuel Garth quipped that the endowment was “about as logical as if a eunuch should found a seraglio.”