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Charlton Depot is a town in Worcester County, Massachusetts, United States. The area was first settled in 1735. It was established as a District separated from Oxford on January 10, 1755, and became a Town in 1775 by a law that made all Districts into Towns. It was named after Sir Francis Charlton. During the 1800s, farming continued to be the major occupation, but woolen mills were being built along some of the town's brooks by the turn of the twentieth century.