Grenfell was born on 16 June 1881 at Penyrheol, Gorseinon, Swansea, the son of William Grenfell and his wife Alice, the daughter of William Hopkins.
He was educated at Penyrheol Board Elementary School; but in 1893, at the age of 12, started work underground in the coal mines. While working he attended night school to study mining, geology and mathematics; and in 1903 he went to Nova Scotia, where he worked with people of many nationalities and laid the foundation of his wide knowledge of languages. While in Canada he passed his Under Managers Certificate; and in 1905 he returned to Britain, where he obtained First Class Managers qualifications.
In December 1905 Grenfell married Beatrice Morgan, daughter of John Morgan of Gorseinon. They had one daughter, Eileen, who was unmarried.
Grenfell continued to work underground until 1916, when he was appointed the Miners Agent for the Western Region of the South Wales Area. He became active in the local Labour Party in 1916; and in 1920 he was adopted prospective candidate for the Gower constituency. He was elected Member of Parliament (MP) in a by-election in 1922, and held the seat until 1959.
"DR", as he was known, was a Member of the Parliamentary Select Committee on Betting, a Member of the Parliamentary Administration Committee, and served on the Forestry Commission and on the Royal Commission of Safety in Mines in 1936. He became Chairman of the Franco/British Parliamentary Party, for which he was later invested with the Chevalier of the Legion of Honour. He acted as Chairman of the Welsh Parliamentary Labour Party, and in Winston Churchill's coalition Government during World War II he served as Secretary for Mines at the Board of Trade, 1940-42. As Minister for Mines, he made the case for the nationalization of the coal industry, and reiterated the call in his 1947 book, Coal.
From 1948 to 1951 Grenfell was Chairman of the Welsh Tourist Holiday Board; and while holding that post he saw Gower become the first area of Britain to be designated an Area of Outstanding Natural Beauty.
In 1951 Grenfell was sworn of the Privy Council.
In 1953 Grenfell became the first Labour politician to hold the title "Father of the House", as the longest continual serving Parliamentarian. This was despite Churchill being older and entering Parliament before him, as Churchill had broken his time as a MP.
Grenfell held office in many local bodies, and was made an Honorary Freeman of Swansea for his contribution to public service. A bust of him now stands in the Swansea Guildhall.
Grenfell was succeeded as Member of Parliament for Gower by his former Agent, County Councillor Ifor Davies of Gowerton, who continued to hold the Gower seat until his death in 1982.
Grenfell's brother, William John Grenfell, was for a number of years a member of Llwchwr Urban District Council, representing the Pontybrenin ward.
David Rhys Grenfell died on 20 November 1968 aged 87, and is buried at Brynteg Cemetery, Gorseinon. His wife, Beatrice, who was a County Magistrate, died around 1970.