The area was originally called Chedabouctou and was the site of one of a fishing post of Nicolas Denys.

A group cleared land and spent the winter with the first crops being planted in 1683.

Louis-Alexandre des Friches de Meneval landed at Chedabouctou in 1687 when arriving to take up his position as governor of Acadia.

The district completely surrounds the Town of Mulgrave and it borders the Municipality of the District of St. Mary's to the west, the Municipality of the County of Antigonish to the north and the Strait of Canso to the east.

Various mining and energy (natural gas) projects have been developed in Guysborough, including around the Southwestern town of Goldboro, Nova Scotia where a $10 Billion liquefied natural gas LNG terminal and pipeline project is being pursued by the Canadian firm Pieridae Energy.