Boydell was born in Dorrington, Shropshire, to Josiah and Mary Boydell (née Milnes) and was educated at least partially at Merchant Taylors' School. His father was a land surveyor and young Boydell, the oldest of seven children, was expected to follow in his footsteps. In 1731, when Boydell was eleven, the family moved to Hawarden, Flintshire. In 1739 he became house steward to MP John Lawton and accompanied him to London. A year later, like many other enterprising young men of the time, Boydell resolved to sail to the East Indies in hopes of making his fortune, but he abandoned the scheme in favour of returning to Flintshire and Elizabeth Lloyd, the woman he was courting. Whether or not he intended to pursue land surveying at this time is unclear.
Around 1747, Boydell published his first major work, The Bridge Book, for which he drew and cut each print himself. It cost one shilling and contained six landscapes in each of which, not surprisingly, a bridge featured prominently. A year later, in 1748, Boydell, apparently financially secure, married Elizabeth Lloyd. The couple did not have any children and Elizabeth died in 1781.
Boydell realized early in his career that his engravings had little artistic merit, saying later that they were collected by others "more to show the improvement of art in this country [Britain], since the period of their publication, than from any idea of their own merits". This may explain why in 1751, when he became a member of the Stationers' Company, he started buying other artists' plates and publishing them in addition to his own. Ordinarily an engraver, such as William Hogarth, had his own shop or took his finished engravings to a publisher. In adopting the dual role of artist and print dealer, Boydell altered the traditional organization of print shops. He was not subject to the whims of public taste: if his engraves did not sell well, he could supplement his earnings by trading in the prints of other artists. He also understood the concerns of both the engraver and the publisher. In fact, as a publisher, he did much to help raise the level of respect for engravers in addition to furnishing them with better paying commissions.
In 1786 he published, by subscription, a series of prints illustrating Shakespeare's plays. The pictures from which these were made were commissioned from the most famous artists of the day, and were exhibited in Boydell's own gallery in Pall Mall. In 1802, the year of the production of Boydell's Shakespeare, the gallery con tained 102 pictures, including canvases by Reynolds, Romney, Opie, Barry, Fuseli; Angelica Kaufmann, Stothard and others. Towards the close of his life Boydell sustained severe losses and was compelled to dispose of his Shakespeare gallery by lottery.