The southern mouth of the Manatee River was likely the landing site of the De Soto Expedition and is the location of the U.S. National Park Service's De Soto National Memorial.

The area was opened to settlement in 1842. The first two settlers were Joseph Braden and Hector Braden who moved into an area near the Manatee River, The two had lost their land for their plantations in Northern Florida during the Panic of 1837. They were said to have heard about that there was abundant land in the area. The brothers moved into a log cabin 5 miles north of the mouth of the Manatee River. Four years later Hector had drowned while trying to cross the Manatee River on his horse during a hurricane. Despite this tragic event, Joseph decided that he would still build his sugar plantation, the Braden sugar mill at the mouth of the Manatee River and the Braden River. He later built a dock where Main Street was at and fortified the area near his house building a stockade.

A few years later in 1851, he would build the Braden Castle, which was made out of tabby and served as his residence. It would later become a popular tourist attraction in the early 1900s with Tin Can Tourists. He would only stay there for the next six years before moving to Tallahassee.

When Manatee County was created in 1855, it included all of what are now Charlotte County, DeSoto County, Glades County, Hardee County, Highlands County, Sarasota County and part of Lee County^.

https://en.wikipedia.org/wiki/Manatee_County,Florida