Henry Hopkins Sibley's grandfather, Dr. John Sibley, served as a medic in Massachusetts in the American Revolutionary War. His wife was Elizabeth Hopkins, whose family name was given as a middle name to their son Samuel and grandson Henry. After her death in 1803, Dr. Sibley was part of an expedition to the Red River country of western Louisiana for the US government after the Louisiana Purchase and chose to settle in Natchitoches. In 1811, his son Samuel Hopkins Sibley and his wife followed to Natchitoches. Samuel Sibley served as a parish clerk from 1815 until his death in 1823.