About 1840 Fort DeSoto was built just to the northeast of where Brooksville is today. In addition to being a military establishment, Fort DeSoto was a trading post and a regular stop on the Palatka-to-Tampa stage line. However, the fort was built on a deep bed of limestone and on-site water was very hard to come by. So some settlers moved about three miles to the south and began the settlement called Pierceville. At the same time, other settlers moved about one mile to the southwest and began the settlement named Melendez. Melendez was the county seat at that time. In 1856, the two settlements merged and formed Brooksville. The town was named after Representative Preston Brooks of South Carolina. Brooks had become famous that year for beating Massachusetts Senator Charles Sumner with a cane in the Senate chambers after Sumner gave a speech very critical of slavery and its southern supporters.

With the advent of the Civil War, the Brooksville area was a staunch supporter of the Confederate cause, contributing cotton, lumber and agricultural products to the Confederacy. In June of 1864, a couple hundred Union troops marched north from the Tampa area and engaged with a Confederate force just outside of town. The Union troops won the engagement easily, then they burned a couple barns and storage buildings before heading to Bayport where they sacked the town and burned several boats used to run the Union harbor blockade. The Brooksville Raid happened in July but is reenacted every year at the Sand Hill Scout Reservation (between Brooksville and Weeki Wachee) in January.

In 1978, the Rogers' Christmas House and Village was opened to the public in Brooksville. The Village is composed of five plantation-era Southern homes (complete with fireplaces) that were moved to the site and arranged to form a traditional Christmas setting. At the time of opening, each house was filled with classic Christmas collectibles. It's still a big tourist attraction.

Parts of Brooksville are still very much "Old Florida" with the historical William Sherman Jennings House, the Judge Willis Russell House and the May-Stringer House (which now also serves as the home of the Hernando County Historic Association). All of these houses are on the National Register of Historic Places.

Between 2000 and 2010, the population of Brooksville rose more than 6%.