He was elected to the House of Commons as MP for Bristol West in 1979. He was regarded as a member of the "wet" or moderate tendency of the Conservative Party, and his progress in Margaret Thatcher's government was slow: He became a Parliamentary Under-Secretary of State at the Department of Education and Science in 1981 before moving to the Department of the Environment in 1983. He remained at Environment, becoming a Minister of State in 1985, until 1988 when he became a Minister of State at the Foreign Office.
He was promoted to the cabinet as Secretary of State for Health in November 1990, just days before Thatcher's resignation, and remained at the cabinet table throughout John Major's time as Prime Minister. He became Chancellor of the Duchy of Lancaster in the Cabinet Office with responsibility for science in 1992, Secretary of State for Agriculture, Fisheries and Food in 1994 and Chief Secretary to the Treasury in 1995.
Lord Waldegrave is the younger son of the 12th Earl Waldegrave, and a brother of the present earl. He is married to Caroline Waldegrave, cookery writer and managing director of Leith's School of Food and Wine.