Born shortly after 1800 in the Great Smoky Mountains, Jesse Bushyhead's ancestry included John Stuart, a British agent to the Indians who had married a Cherokee woman. After attending school in Tennessee, he returned to Amohee, his hometown located on the western edge of the Great Smoky Mountains, as a devout Christian and began preaching to his people. He decided to be baptized by immersion after studying the Bible, and in 1830 a Baptist preacher from Tennessee administered the rite. Bushyhead was instrumental in converting other Cherokees to Christianity and establishing a church at Amohee.
He became a close associate of the Reverend Evan Jones, who recommended him for an assistant missionary position with the Baptist Board of Foreign Missions in 1832. The recommendation was accepted, and Bushyhead held the post for 11 years. Following his April 1833 ordination, he served as pastor of the Amohee church while working with Evans to further missionary efforts and to translate religious works into the Cherokee language. Bushyhead also held a number of high offices among his people and served as his nation's delegate to Washington, D.C., on several occasions. In 1834 he was appointed as a justice of the Cherokee Supreme Court, and from 1838 to 1839 he and Evans were chosen to lead removal groups to Indian Territory (present-day Oklahoma) during the forced migration from their homeland known as the Trail of Tears. They reestablished their mission in the new location and continued their religious efforts.
Bushyhead served as a founder and president of the National Temperance Society among his people, traveled to New York City to address fellow Baptists at an annual meeting of the Baptist Board of Foreign Missions and completed a translation of the book of Genesis, which was published in The Cherokee Messenger. Although a central figure in a controversy over slavery that led to a schism between Northern and Southern Baptists, the Cherokee minister died on July 17, 1844, before the issue was resolved. The belief persisted that he was asked to resign by his missionary board over his alleged ownership of slaves, but that was not the case. According to Jones, Bushyhead had once bought one black family for the purpose of setting them free, and his wife had inherited a female slave who had also been released. Bushyhead was succeeded in his pastorate post by Lewis Downing.
Bushyhead's family included his eldest son, Dennis, who served as a principal chief for two terms between 1879 and 1887. Bushyhead's Cherokee name has also been cited as Tas-the-ghe-tee-hee or Dta-ske-gi-di-hi. He has at times been erroneously identified as John Bushyhead.