Walpole was the eldest son of Prime Minister Sir Robert Walpole, who was created Earl of Orford in 1742, and his first wife Catherine (née Shorter). In 1723, in honour of his father, he was raised to the peerage as Baron Walpole, of Walpole in the County of Norfolk. Between 1733 and 1751 he served as Lord Lieutenant of Devon. In 1745 he succeeded his father as second Earl of Orford.
Lord Walpole married Margaret, daughter of Samuel Rolle, in 1724. He died in March 1751 and was succeeded in his titles by his son George. Lady Walpole became 15th Baroness Clinton in her own right in 1760 when the abeyance of this title was terminated. She had remarried in 1751 and died in 1781.