He was the eldest son of Samuel Clarke (1599–1683), and was born at Shotwick, near Chester, on 12 November 1626.
He was educated at Peterhouse, Cambridge; and was appointed fellow of Pembroke Hall by Edward Montagu, 2nd Earl of Manchester on 13 March 1644.
At the Restoration he held the rectory of Grendon Underwood, Buckinghamshire, from which he was ejected after the Act of Uniformity 1662.
The work of his life was his annotated edition of the Bible, already planned by him as an undergraduate; the notes are brief.
The work had the approval of John Owen, Richard Baxter, Philip Doddridge, George Whitefield, and William Cleaver.