In 1830, he joined a hunting and trapping party at Fort Smith, Arkansas that included George Nidever. Graham attended the Rendezvous at Pierre's Hole and took part in the battle of Pierre's Hole, in present-day Idaho.
From there, Graham's path to California is unclear. He may have joined Joseph R. Walker's party,  or joined one of the groups led by Ewing Young. His son later claimed that Graham came by way of Oregon, while his daughter said he took a southern route through Chihuahua, New Mexico.
In 1836, Graham led a group of American and European immigrants who supported Juan Bautista Alvarado and José Castro in a coup against Mexican Governor Nicolás Gutiérrez. In 1840, Alvarado had Graham arrested, among a group of about 100 foreigners, and sent to Tepic, Mexico for trial and imprisonment. This action led to a diplomatic crisis, involving Mexico, the United States and the United Kingdom, that became known as the "Graham Affair". With the help of a recent arrival in Monterey, Thomas J. Farnham, Graham and the others were eventually released, Graham having been imprisoned for about a year. Farnham later wrote a romanticized account of these events. Some credited the incident with assisting in the formation of an American political justification for its eventual annexation of California. 
In 1841, upon his return from Mexico, Graham moved north to the Santa Cruz area, where he established another distillery at Rancho Zayante, near the present-day community of Felton. With help from Danish-immigrant Peter Lassen, Graham built one of the first water-powered sawmills in California. Part of Graham Hill Road, now a major route between Felton and Santa Cruz, was built by Graham to transport his timber to the coast for shipment.
Although not a Mexican citizen, Graham was able to purchase the Rancho Zayante land by proxy through his fellow frontiersman Joseph Majors, owner of the adjacent Rancho San Agustin. Other former mountain men and Graham associates were also at Zayante, including Job Francis Dye, who later dictated a memoir including some adventures he shared with Graham. 
Early in 1846, a U.S. Army exploring mission led by John C. Fremont stopped at Graham's Zayante community. Mexican authorities feared that Fremont's hidden purpose was to stir up anti-government sentiments among the Americans there, and Fremont was soon forced to leave California for Oregon. He returned later in the year, after the Mexican–American War began, to recruit volunteers for the California Battalion. Graham himself, at age 46, did not volunteer.
In 1851, Graham purchased Rancho Punta del Año Nuevo, on the coast north of Santa Cruz.
Isaac Graham died in 1863, and is buried at Evergreen Cemetery in Santa Cruz. 
|Wikisource has original text related to this article:|
- Nunis, Doyce Blackman. The Trials of Isaac Graham, Dawson's Book Shop, 1967. OCLC: 1016212.
- Bancroft, Hubert Howe. History of the Pacific States of North America, Vol. XVI: California, Vol. IV: 1840-1845.; The History Company, San Francisco; 1886. (retrieved 4 Mar 2010).
- Narrative of the Adventures of Zenas Leonard
- Captain Isaac Graham.
- Early Sentiment for the Annexation of California... By Robert Glass Cleland. The Southwestern Historical Quarterly, Vol. 18, No. 1 (Jul., 1914), pp. 20-25. Downloaded Sept. 10, 2019.
- Santacruzmah.org: "Job F. Dye — Biography", Santa Cruz Sentinel, May 1, 1869.
- Evergreen Cemetery, Find-a-Grave