In his youth Houston moved with his family to a farm in rural Tennessee after the death of his father in 1807. He ran away in his mid-teens and lived for nearly three years with the Cherokee Indians in eastern Tennessee, where he took the name Black Raven and learned the native language, skills, and customs. Houston thus developed a rapport with the Indians that was unique for his day. As a consequence, after service in the War of 1812 and an interlude of study and teaching, in 1817 Houston became a U.S. subagent assigned to manage the removal of the Cherokee from Tennessee to a reservation in the Arkansas Territory. He returned to Nashville to practice law and from 1823 to 1827 served as a U.S. congressman. He was elected governor of Tennessee in 1827. After a brief unsuccessful marriage to Eliza Allen in 1829, he resigned his office; he again sought refuge among the Cherokee and was formally adopted into the tribe. He twice went to Washington, D.C., to expose frauds practiced upon the Indians by government agents and in 1832 was sent by Pres. Andrew Jackson to Texas, then a Mexican province, to negotiate Indian treaties for the protection of U.S. border traders.

Houston's arrival in Texas coincided with the heated contest between U.S. settlers and Mexicans for control of the area. He established a home there by 1833, and he quickly emerged as one of the settlers' main leaders. When they rose in rebellion against Mexico in November 1835, he was chosen commander in chief of their army. The revolt suffered reverses during the winter, but on April 21, 1836, Houston and a force of fewer than 800 Texans surprised and defeated 1,600 Mexicans under Gen. Antonio López de Santa Anna at San Jacinto. This triumph secured Texan independence and was followed by Houston's election as president (1836–38; 1841–44) of the Republic of Texas. He was influential in gaining the admission of Texas to the United States in 1845. Houston was elected one of the new state's first two senators, serving as a Union Democrat from 1846 to 1859. His views on the preservation of the union were unpopular with the Texas legislature, however, and on the eve of the Civil War he was not reelected—although he was chosen governor once more in 1859. In this position he tried unsuccessfully to prevent the secession of his state in 1861, and upon his refusal to swear allegiance to the Confederacy, he was declared deposed from office in March.

He spent his last two years quietly at home in Huntsville with Margaret Lea, his wife from 1840 and mother of his eight children. The city of Houston, Texas, was named in his honour.