He was born in Rockbridge County, Virginia. Receiving only a basic education he emigrated with his family to Tennessee in 1807, following the death of his father. He ran away from home in 1809 and resided for a time with a Cherokee tribe, where he was named "the Raven". In March 1813 he joined the U.S. Army to fight the British in the War of 1812, by December he had risen from Private to Third Lieutenant. He was severely injured at the Battle of Horseshoe Bend in March 1814. Following his recovery he was assigned as an Indian agent to the Cherokees. He left the army in March 1818.
Following six months of study he opened a legal practice in Lebanon, Tennessee. He was made attorney general of Nashville district in late 1818 and also given a command in the state militia. In 1823 he was elected to the House of Representatives for Tennessee, where he was a staunch supporter of Andrew Jackson. He was re-elected in 1825 before leaving to take up the post of governor of Tennessee in 1827. He intended to stand for re-election in 1829 but following a eleven week marriage to Eliza Allen he abruptly resigned (the actual divorce was not until 1837). He spent a time among the Cherokee, took a Cherokee wife and setting up a trading post, apparently drinking heavily the entire time. Following a trial for assault in Washington he left the Cherokee and his wife to enter Mexican Texas in December 1832.
He was immediately swept up in the political turmoil of the state, he attended the Convention of 1833 as representative for Nacogdoches and emerged as a radical, supporting William Harris Wharton and his brother. He also attended the Consultation of 1835. He was made a Major General, of the Texas Army in November 1835, then Commander-in-Chief in March 1836. He negotiated a settlement with the Cherokee in February 1836.
Following the Texas Declaration of Independence in March, Houston joined his volunteer army at Gonzales and was soon forced on the retreat in the face of the forces of Antonio Lopez de Santa Anna. But at the Battle of San Jacinto on April 21, 1836 the careless Mexicans were surprised and heavily beaten, Santa Anna was captured the following day. Houston briefly remained for negotiations before retiring to the United States for treatment on a ankle wound.
Using his popularity Houston was elected president of the Republic of Texas on September 5, 1836 and served from from October 22, 1836 to December 10, 1838, and from December 12, 1841 to December 9, 1844. He put down the Cordova Rebellion of 1838 and while intially seeking annexation by the U.S. he dropped that hope during his first term. In his second term he strove for financial prudence and worked to make peace with the Indians and avoid war with Mexico, following the two invasions of 1842. He had to act over the Regulator-Moderator War of 1844 and sent in the militia. The settlement of Houston was founded in 1836, named in his honour and served as capital. Between his presidential terms (the constitution did not allow a president to serve consecutive terms), he was a representative in the Texas House of Representatives for San Augustine, a major critic of President Mirabeau Lamar. In 1840 he married Margaret Moffette Lee, they had eight children and she acted as a temperant influence on Houston.
After annexation in 1845, he was elected to the U.S. Senate together with Thomas Jefferson Rusk. Houston served served there from February 21, 1846 until March 4, 1859. He was considered a potential candidate for president. But, despite the fact that he was a slave-owner, his strong Unionism and opposition to the extension of slavery alienated the Texas legislature and other southern States, especially with his support of the Oregon Bill (1848) and the Compromise of 1850 and his opposition to the Kansas-Nebraska Act. He was a lame duck senator from 1857.
He ran for governor of Texas, unsuccessfully in 1857 and successfully in 1859, making him the only person in U.S. history to be the governor of two different states. He resigned in March 1861 following his refusal to take an oath of loyalty to the Confederacy; he was replaced with Edward Clark having refused the use of force to prevent the secession.
In 1862 he retired to his farm at Huntsville, where he died in the following year.