Until 1810, the library housed books covering a wide range of subjects, but under George Williams it narrowed its focus to the sciences.

William Pittis, Radcliffe's first biographer, ascribes the change of heart to excessive demands from the Rector and Fellows of Exeter College.

[7] A number of tenement houses fronting Catte Street, built right up to the schools, some gardens, Brasenose College outbuildings and Black Hall occupied the site required for the library.

[6] The negotiations dealing with Catte Street took over twenty years, with the final payments being made to Oriel, Magdalen and University colleges in 1737 (N.S.).

[8] Radcliffe had placed four men in charge of his estate: William Bromley, sometime Speaker of the House of Commons; Sir George Beaumont, a Lord of the Admiralty; Antony Keck, a banker; and Thomas Sclater Bacon, a lawyer.

[8] There appears to have been some difficulty in getting the required majority to agree to work beginning before 1736, with the four split between Bromley and Beaumont wanting to start and Bacon and Keck set against them.

The early start was to be funded by the high share price of investments in the South Sea Company, which proved overly optimistic.

[11] On 4 March 1737, the Trustees directed Gibbs along with Francis Smith of Warwick and William Townesend of Oxford 'to prepare Stones and things ready for building the library'.

An early set of plans were engraved and prints delivered to the most important members of the town and University, no doubt to ensure that their opposition was dealt with swiftly.

An extract states:[6]Mr. William Townesend 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.

A portrait of Radcliffe was sent to John Michael Rysbrack, who was tasked with creating a six-feet tall marble statue of the Library's benefactor.

[18] The Trustee's meeting of 13 March 1746 reveals that the remaining work consisted of the paving of the library inside and out, the staircase rail, and the locks, hinges and bolts for the bookcases.

[23] The first porter was Pudsey Mussendine, who was paid a salary of £20 per annum, and received a gown in Radcliffe's colours and with his coat of arms emblazoned on it.

In 1750, part of the land between the Camera and St. Mary's Church was remodelled to remove a dividing wall, level the ground and lay pebbles on it.

Only 14 were actually erected and in 1755 the Trustees reimbursed the University for the cost of maintaining them up to that point and took on the obligation itself out of the £100 per annum left by Radcliffe for the Library's upkeep.

[6] A muniment room was created in 1753 to house the collection documents relating to Radcliffe's will and the accumulated deeds of the land on which the library had been built.

Although the Trustees did not believe that the particular documents lost were likely to cause many future problems, the remaining manuscripts were moved to the main Library to prevent further damage.

There was, however, one controversial benefaction of a series of marbles, with a custodian appointed and funded (along with the cost of securing the statues) by Sir Roger Newdigate.

[40] Williams, a physician in the Radcliffe Infirmary and Professor of Botany, adopted an approach which had been mooted a couple of years before to fill the library's shelves not with a general collection of works, but rather specifically scientific books.

Dr. Abraham Robertson was asked to donate a copy of the Radcliffe Observatory's records each year in exchange for being allowed to borrow certain books.

[42] The grounds of the library were enclosed by railings in 1827 at a cost of £1,310, although the ascertainment of the exact extent of the Trustee's holdings required careful examination and a previous overlooked transfer completed.

[43] Upon Williams' death in 1834, the Trustees gave an unprecedented statement of thanks; it was echoed by a report in The Gentleman's Magazine which read: "In carrying into effect these great national as well as academic purposes, the Trustees found in Dr. Williams's extensive reading, retentive memory... exact judgment, comprehensive views and philosophical mind, the very talents and accomplishments which were necessary to ensure the successful execution of their design".

[45] Gas heating and lighting was introduced into the library, a third member of staff (an assistant) hired at a salary of £25 per annum, and insurance taken out against the risk of fire – £10,000 to cover the buildings and a further £10,000 for the books.

He made several structural alterations, creating a reading room, improving the lighting and heating and adding a hot water system.

[49] More significantly, in light of the sum of £200 to be spent on books annually, which Acland considered insufficient, he set out a detailed proposal to bring the library under the leadership of the university.

[6] It now holds books from the English, history, and theology collections, mostly secondary sources found on Undergraduate and Graduate reading lists.

In November 2010, the building was occupied by students for over twenty-four hours, as part of wider national protest against proposed changes to university funding and substantial increases in the cost of tuition.

[55][56] In October 2023, the building was sprayed with orange paint in a protest by Just Stop Oil against Oxford University's links to fossil fuel companies such as Ineos.

The arcade arches were fitted with iron grilles: three of them were gates which were closed at night, and which gave access to the library by a grand staircase.

[20] Gibbs later said of the Trustees: "I never observed a trust discharged with greater unanimity, integrity and candor, during the whole time I had the honour of serving you, from the laying of the first stone of this fabric to its finishing.