Jesse Applegate was born in Kentucky and attended the Rock Creek Seminary in Illinois. He later worked as a school teacher and a clerk before serving as deputy surveyor to the Missouri surveyor general. In 1832 he married Cynthia Ann Parker who became mother to their 13 children. Applegate's brothers, Charles and Lindsay, and their families joined Jesse and his family on the Oregon Trail in what was known as the "Great Migration" of 1843. Jesse led a company of immigrants across the plains and mountains to The Dalles on the Columbia River in Oregon. The next year he started a farm in what is now western Polk County. He also built a mill and worked as a surveyor, including the 1844 survey of the Oregon City townsite.

Applegate played a key part in opening the South Road to Oregon that is also known as the Applegate Trail (Scott-Applegate Trail). The route started at Fort Hall in present day Idaho and followed the Humboldt River before crossing the Klamath Basin. Advocates saw it as a way to encourage settlement in southern Oregon and the upper Willamette Valley. The route had fewer obstacles for wagons than the northern route to the Willamette Valley but offered its own set of problems.

Oregon politics attracted Applegate's attention beginning in 1845 with his service in the provisional government where he helped in the complete revision of the government that increased its influence in the Oregon Country. He later helped shape the development of the Oregon Territory as part of the United States and worked to elect Abraham Lincoln president.

Applegate settled on a land claim in the Umpqua Valley in 1849 in a place he called Yoncalla after the local Indian tribe. There he farmed and raised cattle. A student and writer, Applegate maintained a large library in his house. He continued his influence over public issues and gained the title "Sage of Yoncalla" from his friends.