The area is believed to be lived in by humans as early as 9000 B.C.  When the Spanish first came to the area, it was inhabited by Indians who spoke Muskegon.  In the early 1700's  southern Creek Indians (better known as Seminoles) moved into the area.  Evenly they were joined by groups of escaped slaves.  In the first half of the nineteenth century they where forced to move to Oklahoma or driven south to Everglades.

The principle communities are Dade City, Zephyrhills, New Port Richey, Port Richey, and San Antonio. Dade City was known as Fort Dade until 1881 when the Fort Dade Postmaster's Commission was transferred to Fort Dade community a few miles west. Zephyrhills was established in 1911 as a retirement center for veterans of the Union Army. New Port Richey was founded in 1915 adjacent to the older town of Port Richey, established by Captain Aaron Richey in the 1880's. San Antonio was developed as the center of the "Catholic Colony" by Judge Edwin Dunne in 1881. Holiday appeared as part of the extension development of the county's west coast in the 1960's.

In the era of the Second World War, the development of Pasco Packing Company (now Lykes-Pasco) and later of Evens Packing Company in Dade City gave the county two of the largest citrus packing plants in the world. The procedure for making orange juice concentrate was, to a large degree, developed at Pasco Packing Company.

The coastal portion of the county was largely undeveloped until the second half of the twentieth century when it became favored as a retirement area. In recent years, huge residential developments have appeared around U.S. Highway 19, causing the county's population center to shift to the west coast.