In 1838 Frémont assisted the French scientist Jean-Nicolas Nicollet (Nicollet, Joseph Nicolas) in surveying and mapping the upper Mississippi and Missouri rivers. He also headed an expedition (1841) to survey the Des Moines River for Nicollet, who had given him expert instruction in geology, topography, and astronomy. His growing taste for wilderness exploration was whetted by the expansionist enthusiasm of Missouri senator Thomas Hart Benton (Benton, Thomas Hart), who became his adviser, sponsor, and, in 1841, father-in-law. Benton's influence in government enabled Frémont to accomplish within the next few years the mapping of much of the territory between the Mississippi valley and the Pacific Ocean. In 1842 the War Department sent him to survey the route west to Wyoming, and in 1843, accompanied by the colourful guide Kit Carson and mountain man Thomas Fitzpatrick, he completed a survey to the mouth of the Columbia River. After thoroughly exploring much of the Northwest, he made a winter crossing of the Sierra Nevada to California, further adding to his fame.

War with Mexico (Mexican-American War) over the annexation of Texas seemed imminent, and in the spring of 1845 Frémont headed a third expedition west with secret instructions for action in case of war. Upon his arrival in California he defied Mexican authorities, throwing his support behind a small group of dissident Americans near Sonoma who started an unofficial uprising and created the Bear Flag (Bear Flag Revolt) Republic. When news of the declaration of war with Mexico (May 1846) reached California, Frémont was appointed by Commodore Robert F. Stockton (Stockton, Robert F.) as major of a battalion and, with Stockton, completed the conquest of the future 31st state. Meanwhile, General Stephen Watts Kearny entered California from the southeast with orders to establish a government, leading to an obvious conflict of authority. Frémont accepted California's capitulation from Mexican officials at Cahuenga Pass, near Los Angeles, and Stockton appointed him military governor of California. Kearny, however, had Frémont arrested and court-martialed in Washington, D.C., in 1847–48 for disobedience. He was sentenced to dismissal from the army, and although his penalty was set aside by President James K. Polk, Frémont resigned. Through it all, he retained the high regard of the general public.

Frémont became a multimillionaire in the 1848 California gold bonanza, and in 1850 he was elected one of the state's first two senators. A firm opponent of slavery, he was nominated for the presidency in 1856 by the new Republican Party. In the election he was defeated by the Democratic candidate, James Buchanan, but he came closer to uniting the electorate of the North and West against the South than had any previous candidate.

Frémont served unsuccessfully as a Union officer in the American Civil War, and he resigned from the army (1862) a second time. Still popular, he was considered for the presidential nomination again in 1864 but withdrew to avoid dividing the party. Thereafter he retired from public life to devote himself to railroad projects in the West. In 1878, after losing his fortune, he was appointed governor of the Arizona Territory, where he served until 1883.