Born near Sullivan, Missouri, he attended public school and graduated from the Franklin County Mining School in 1838; nevertheless, he is remembered as "almost illiterate" , with a taste for poker, bourbon, and tobacco.

Upon news of the discovery of gold at Sutter's Mill, Hearst moved to California (according to some reports, he walked the entire way). After arriving in 1850, he became a highly successful prospector, and otherwise engaged in mining, stock raising and farming in Nevada County. As head of Hearst, Haggin, Tevis and Co., he had interests in the Comstock Lode in Nevada, the Ophir mine in Nevada, the Ontario silver mine in Utah, the Homestake gold mine in South Dakota (his pursuit of which is portrayed in the HBO television series Deadwood), and the Anaconda copper mine in Montana. (A later investment was the Cerro de Pasco Mine in Peru.) The company grew to be the largest private firm of mine-owners in the United States. Hearst himself acquired the reputation of being the most expert prospector and judge of mining property on the Pacific coast, and contributed to the development of the modern processes of quartz and other kinds of mining. Another of his holdings, that his son insisted on taking control of, was the San Francisco Examiner, which later became the foundation of the Hearst publishing empire.

He moved to San Francisco in 1862, and married Phoebe Apperson. She gave birth to their only child, William Randolph Hearst, in 1863. Hearst was a member of the California State Assembly from 1865 until 1866. During this time he acquired the 48,000 acre (194 km²) Piedras Blancas Ranch at San Simeon, California in 1865. He later bought the adjoining ranches, and this land eventually became the site of the famed Hearst Castle.

He was an unsuccessful Democratic candidate for Governor of California in 1882.

He was appointed as a Democrat to the United States Senate to fill the vacancy caused by the death of John F. Miller and served from March 23, 1886, to August 4, 1886, when a successor was elected; elected in 1887 to the United States Senate as a Democrat and served from March 4, 1887, until his death in Washington, D.C. in 1891.

He is buried with his wife and son in Cypress Lawn Cemetery, in Colma, California. The Hearst Memorial Mining Building is dedicated to his memory.