While there is evidence of earlier Pawnee settlements near the salt wells in Salina, the area was established as a premier port and trading post by Jean-Pierre Chouteau in 1796. It was considered to be the first major outpost in the region and quickly grew with the addition of homes, a port and active trading. By the early 19th century, Salina grew into an established regional trading center with significant trade occurring between Fort Smith and New Orleans, and the hub for negotiations occurring between the United States and the Osage Nation (1830).

Captain John Rogers operated the Salina saltworks between 1830 and 1843. These saltworks consisted of salt kettles, furnaces, and piping. The sale of salt, in addition to the fur trade, created the demand for the areas first post office in 1849. After his tenure and dispossession by the Cherokee Council, the saltworks was leased and operated by Lewis Ross, brother of Chief John Ross. During his operations, Ross constructed a plantation home and expanded his property to include gardens, cotton fields, mills and farm buildings. This home eventually became the Cherokee Orphan’s asylum in 1872.

By the early 20th century, Salina had grown to include approximately 550 residents, two general stores, a post office, livery, blacksmith, dry goods store, several schools and churches. It also hosted the ferry built and operated by S.H. Mayes which crossed the Neosho/Grand River and docked at Ferry Street.

Several of these sites still exist today in some form and are either protected through the National Register or have markers delineating their locations.