Fremont had been sent west in 1845 by the War Department to survey the Great Basin and Alta California, then a possession of Mexico. His mission was ostensibly scientific, but his father-in-law, Senator Thomas Hart Benton of Missouri, was a leading voice for Manifest Destiny - the belief that America was destined to rule the continent. Fremont spent months in northern California, provoking Mexican authorities and stoking patriotic sentiment among American settlers. On March 30, 1846, his band reached the Lassen Ranch in the upper Sacramento Valley, where settlers claimed a force of 1,000 Native Americans was preparing to attack white settlements. No evidence supported this claim, but Fremont moved his men upriver in search of the supposed threat.

Fremont's party consisted of 60 white men, nine Delaware Indians, two California Indians, and five traders - each carrying a rifle, two pistols, and a knife. When they spotted the large Wintu encampment near Reading's Ranch, Fremont ordered an advance from three sides. The Wintu, their camp filled with women and children, were pinned against the river with no escape. The men formed a defensive line while their families huddled behind them. Fremont's riflemen opened fire from a distance the Wintu arrows could not reach, then closed in with sabers and pistols. Expedition member Thomas Breckenridge later wrote that the settlers "charged into the village taking the warriors by surprise and then commenced a scene of slaughter which is unequalled in the West. The bucks, squaws and paposes were shot down like sheep."

Those who survived the initial volleys fled for the hills or plunged into the Sacramento River. Mounted men chased down the runners and killed them with tomahawks. Riflemen lined the riverbank, shooting at swimmers trying to reach the opposite shore. Eyewitness William Isaac Tustin called it simply "a slaughter." Estimates of the dead vary wildly: expedition members claimed 120 to 175 killed, while Tustin reported 600 to 700 dead on land and another 200 or more drowned or shot in the water. No expedition member was killed or even wounded. Breckenridge, who claimed he did not participate, wrote: "It takes two to fight or quarrel but in that case there was but one side fighting and the other side trying to escape."

Neither Fremont nor his men faced any consequences for the massacre. They continued upriver, killing Native Americans they encountered. A month later, Fremont participated in the Klamath Lake massacre after three of his men were killed in retaliation by the Klamath people. By August 1846, American forces had occupied California, and in January 1847, Fremont briefly served as Military Governor. He became California's first U.S. Senator in 1850 and ran for president in 1856 as the Republican Party's first nominee. Meanwhile, the Wintu faced continued devastation. Through the 1850s, large-scale massacres including the Kabyai Creek massacre, the Old Shasta Town massacre, and the Bridge Gulch massacre killed hundreds more. The Sacramento River massacre was not an isolated incident - it was the opening chapter of the California genocide.