She first became famous after playing the lead in a 1962 BBC adaptation of What Katy Did. Soon afterwards, she was taken up by Walt Disney, and starred in The Three Lives of Thomasina opposite Patrick McGoohan and The Fighting Prince of Donegal. She would later appear opposite McGoohan in two linked episodes of Danger Man.

Susan Hampshire is best known for her work on television. Hampshire appeared in several popular television serials, notably in the BBC's blockbuster, The Forsyte Saga (1967), in which she played Fleur. In 1969, she starred as Sarah Churchill in The First Churchills, and in 1974, she played the lead in another 26-part serial, The Pallisers. When shown in the United States in the 1960s and 1970s these series helped establish public broadcasting and the program Masterpiece Theatre as major cultural forces. Ms. Hampshire received Emmy Awards from the Academy of Television Arts & Sciences for her roles in The Forsyte Saga (1970), The First Churchills (1971), and Vanity Fair (1973). She played Esme Harkness in the 1997 TV series, The Grand. Her most recent TV series was Monarch of the Glen. Ms. Hampshire has also been active on the stage over the years.

Until her autobiography, Susan's Story, few people were aware of her struggle with dyslexia. Hampshire is a prominent campaigner in the UK on dyslexia issues. In 1995, she was appointed an OBE (Officer of the Order of the British Empire) in connection with that work.

Susan Hampshire was married to the French film producer Pierre Granier-Deferre from 1967 to 1974. They had a son and a daughter, but the daughter died in infancy. She has been the wife of theater impresario Sir Eddie Kulukundis since 1981.