She was the daughter of Sir John Shorter, (born 1660), a wealthy merchant from Kent, and Elizabeth Philipps, (born c. 1664). She was the granddaughter of Sir John Shorter (1625-1688), Lord Mayor of London in 1687. On her marriage to Walpole in 1700 she paid a dowry of £20,000.
She was renowned for her extravagant lifestyle, frequently attending the opera and buying expensive clothes and jewellery, but the couple became estranged during his during his Prime Ministership, and he had a succession of mistresses. He lived with Maria Skerrett in both Richmond and Houghton Hall in Norfolk while Lady Walpole was still alive. She herself courted controversy when it was noted that the Walpoles' youngest son Horace, born 10 years after his siblings when the marriage was cool, did not share looks or character with any siblings or his father. Lady Walpole's lover at that time was reported to be Lord Hervey.