Walton was born in Dungarvan, County Waterford to a Methodist minister father. He attended day schools in Cookstown and Tyrone before becoming a boarder at Methodist College Belfast (Methody) in 1915 where he excelled at mathematics. He became a fellow of Trinity College, Dublin, in 1934, and was appointed Erasmus Smith's Professor of Natural and Experimental Philosophy in 1946. In 1960 he was elected Senior Fellow.
He and John Cockcroft were awarded the 1951 Nobel Prize for work on the transmutation of atomic nuclei by artificially accelerated atomic particles carried out in the Cavendish Laboratory in the University of Cambridge.