The area now known as Fresno County, once a semiarid steppe, was discovered by Spaniards during a search for suitable mission sites. In 1846, this area became the property of the United States as a result of the Mexican War.

Fresno County was formed in 1856 from parts of Mariposa, Merced and Tulare counties. The county is named after Fresno Creek. Fresno in Spanish signifies "ash tree" and it was due to the abundance of mountain ash or ash trees in the county that it received its name. Parts of Fresno County's territory were given to Mono County in 1861 and to Madera County in 1893. The original county seat was placed in Millerton, but it had to be abandoned after a devastating flood swamped the county court house. The county seat was then moved to higher ground at Fresno and the little town of Millerton never fully recovered.

The settling of Fresno County was not without its conflicts, land disputes, and other natural disasters. Floods caused immeasurable damage elsewhere and fires also plagued the settlers of Fresno County. In 1882, the greatest of the early day fires wiped out an entire block of the city of Fresno, and was followed by another devastating blaze in 1883.

At the same time residents brought irrigation, electricity, and extensive agriculture to the area. Moses Church developed the first canals, called "Church Ditches," for irrigation. These canals transformed the barren desert of Fresno County into rich soil, thus enabling extensive wheat farming in Fresno County. Frances Eisen, leader of the wine industry in Fresno County, also began the raisin industry in 1875, when he accidentally let some of his grapes dry on the vine. A.Y. Easterby and Clovis Cole (aka the "Wheat King of the Nation") developed extensive grain and cattle ranches. These and other citizens laid the groundwork for the cultivation of Fresno County - now the nation's leading agricultural region. In more recent times cotton became a major crop in Fresno and the southern San Joaquin Valley, but recent drought and lower demand have lessened cotton's importance to the local economy.

The discovery of oil in the southwestern part of the county, near the town of Coalinga at the foot of the Coast Ranges, brought about an economic boom in the first decade of the 20th century, even though the field itself was known at least as early as the 1860s. By 1910, Coalinga Oil Field, the largest field in Fresno County, was the most richly productive oil field in California; a dramatic oil gusher in 1909, the biggest in California up until that time, was an event of sufficient excitement to cause the Los Angeles Stock Exchange to close for a day so that its members could come by train to view it. The Coalinga field continues to produce oil, and is currently the eighth-largest field in the state.^[2][3]

To date, over thirty structures in Fresno County are on the National Register of Historic Places, including the Fresno Water Tower, which once held over 250,000 US gallons (950 m³) of water for the city of Fresno, the Meux Home, and Kearney Mansion Museum.