The area now known as Manatee County had been inhabited by Native Americans for thousands of years. The southern mouth of the Manatee River was likely the landing site of the De Soto Expedition in 1539 and is now the location of the U.S. National Park Service's De Soto National Memorial.
This area was opened to settlement in 1842. The first settler of Anglo-Saxon decent was reportedly, Josiah Gates, an innkeeper from Fort Brooks (present day Tampa). He arrived in the spring of 1842 with his family. He built a large house, a cabin for a slave family, and enclosures for his animals. Later Henry Smith Clark established the first store and dock. 
Dr. Joseph Braden, came from Tallahassee with his brother, Hector Wother 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 this 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. He would only stay there for the next six years before moving to Tallahassee. Manatee County had the Gamble Plantation, a sugar plantation that was one of the South's finest. Continue Early History.
When Manatee County was created 9 Jan 1855 (from Hillsborough Co.), it included all of what are now Charlotte County, DeSoto County, Glades County, Hardee County, Highlands County, Sarasota County and part of Lee County -  These other counties were created in the following years:  DeSoto County (1887), Charlotte County (1921), Glades County (1921), Hardee County (1921), Highlands County (1921), and Sarasota County (1921). 
This section will provide a researcher with information and links to local sources. Areas covered and of interest to a researcher are (page under development - more to come):