The parish includes Segsbury Camp, an Iron Agehill fort on the crest of the Downs just over a mile south of the village. The Domesday Book of 1086 records Letcombe Regis. The name may come from the Old EnglishLedecumbe meaning the "lede in the combe" – i.e. "the brook in the valley."
"Regis" may derive from the Latin 'rex' meaning 'Royal' with 'Regis' meaning The King's, giving, perhaps, "The Kings brook in the valley."
From 1959 to 2002 the Letcombe Laboratory, a major centre for plant research, was located at the Letcombe Manor Estate. The centre was initially a UK government laboratory, but was sold to the chemical company Dow Elanco in 1985.