Vertue was born in 1684 in St Martin-in-the-Fields, London, his father, perhaps a tailor, and mother are noted as 'Roman Catholic'. At the age of 13, he was apprenticed to a prominent heraldic engraver of French origin who became bankrupt and returned to France. Vertue worked seven years under Michael Vandergucht, before operating independently. He was amongst the first members of Godfrey Kneller's London Academy of Painting, who had employed him to engrave portraits. It was there that he became a pupil of Thomas Gibson, a leading portrait painter.
Vertue had a deep interest in antiquarian research, and much of his labour was given to this subject. From 1713 on, Vertue was a keen researcher on details of the history of British art, accumulating about forty volumes of notebooks. He was a member of the Rose and Crown Club, with William Hogarth, Peter Tillemans and other artists and connoisseurs, and kept some records of it. His travels to sites across England, with enthusiasts such as Edward Harley (Earl of Oxford), Lord Coleraine and others, were recorded in Vertue's highly detailed drawings and notes. In 1717 he was appointed official engraver to the Society of Antiquaries, the same year as its formal foundation. Most of the illustrations in Vetusta Monumenta, up to his date of death, are his work.
After the death of the Earl of Oxford in 1741, Vertue was patronised by the Duchess of Portland and others. The Duke of Norfolk commissioned a work after Van Dyck of the Earl of Arundel and his family. He produced a catalogue detailing the collections of the royal family, at the request of Frederick, Prince of Wales, an avid buyer of the engraver's work.
A portrait of Vertue was painted in 1715 by Gibson, his widow donated this to the Society of Antiquaries; Vertue had produced an engraving of this. A later painting, of the artist aged around 50, by Jonathan Richardson was acquired by the National Portrait Gallery, a plate of this by
Thomas Chambers was engraved for Walpole's Anecdotes. An 1849 edition of Walpole's book contained an engraving, by George Thomas Doo, of a self-portrait—sitting in a library—that shows him displaying a portrait of the Earl of Oxford; this was previously published in 1821 as a lithograph. Another self-portrait, with his wife on their wedding-day, was etched by William Humphrey. Richardson also drew the profile used in James Basire's plate in Nichols's Literary Anecdotes.
Vertue died in London on 24 July 1756 and was buried in Westminster Abbey.
Vertue's brother James (d. 1765) was an artist in Bath who produced the interior view of the abbey that was engraved by him. The second of his three brothers, Peter, was a dancing master of Chelmsford.