The town was founded in 1816 by John Walter Basye and named after his daughter, Louisiana Basye. Other notable early residents were Samuel Caldwell and Joel Shaw, both of whom purchased land from Basye in 1818. All three properties became the original town plat and comprised mainly riverfront properties. Many of the town's residents trace their ancestry to these town pioneers. Louisiana proved to be a profitable shipping point on the Mississippi River, and that wealth led to numerous substantial antebellum homes. Many of those still remain and, along with the Georgia Street Historic District in downtown Louisiana, are listed on the National Register of Historic Places. The Missouri Department of Natural Resources has noted that the town has "the most intact Victorian Streetscape in the state of Missouri."