Spence was elected as the Oxford Professor of Poetry on 11 July 1728, holding the post for maximum term allowed (ten years).

Recommended by Alexander Pope, Spence became a travelling companion of Charles Sackville, 2nd Duke of Dorset and 1st Earl of Middlesex, on a Grand Tour lasting from December 1730 to July 1733.

On his return to Oxford he lectured and made mundane contributions to poetry collections marking royal weddings, births, and deaths.

Spence was a companion to John Morley Trevor in his tour of the Netherlands, Flanders, and France between May 1737 and February 1738, and between September 1739 and November 1741 travelled in Italy with Henry Pelham-Clinton, the Earl of Lincoln.

On 4 June 1742 Spence was appointed Regius Professor of Modern History and exchanged Birchanger for Great Horwood, Buckinghamshire, which he visited each year and distributed charity.

Spence continued to live at Byfleet and spent more than the minimum time required for his prebendal duties of three weeks' residence at Durham.

Spence suffered a mild stroke during his annual journey north in June 1766, and made his will at Sedgefield, Durham, on 4 August 1766.

Spence's unpublished works include his edition of travelling letters, notes for a gardening treatise, notes for a biographical history of English poetry, and his anecdotes, which include tales about Alexander Pope and other literary figures such as John Arbuthnot, Isaac Newton, and Stephen Duck.