In 1850 he migrated to California, where his interest in a colonization scheme in Lower California developed into filibustering plans. On Oct. 15, 1853, he sailed from San Francisco with a small force. After landing at La Paz, he proclaimed Lower California and Sonora an independent republic. Lack of supplies and Mexican resistance forced him back to the United States in May 1854. Exactly a year later he sailed again, this time to Nicaragua at the invitation of a revolutionary faction. By the end of 1855 his military successes made him virtual master of Nicaragua, which was then a key transport link between Atlantic and Pacific ocean shipping.

When Walker arrived in Nicaragua, Cornelius K. Garrison and Charles Morgan, officers of Cornelius Vanderbilt's Accessory Transit Company, gave Walker financial assistance in a plot to gain control of the company. In return, Walker seized the company's property on the pretext of a charter violation and turned it over to Garrison and Morgan. Walker became president of Nicaragua on July 12, 1856, and maintained himself against a coalition of Central American states until May 1, 1857. In order to avoid capture, he surrendered to the United States Navy and returned to the United States.

In November he led another foray but was arrested and returned to the United States as a prisoner on parole. On his third descent on Central America (1860), he landed in Honduras, where he was taken prisoner by the British Navy. He was then turned over to Honduran authorities, who executed him.