Although the Chickasaw settled the area now known as Huntsville around 1300, a combination of factors, including disease, land disputes between the Choctaw and Cherokee, and pressures from the United States government had largely depopulated the area by the time Revolutionary War veteran John Hunt settled around Big Spring in 1805.

After Leroy Pope purchased the area in 1806, he named it Twickenham after the home village of his distant kinsman Alexander Pope. Twickenham was carefully planned, with streets laid out on the northeast to southwest direction based on the flow of Big Spring. However, due to anti-British sentiment during this period, the name was changed to "Huntsville" to honor John Hunt, who had been forced to move to other land south of the new city.

Huntsville served as temporary capital from 1819 to 1820 for the first state constitutional convention. Cahaba, now a ghost town, was the first permanent state capital from 1820 to 1825.

The land in and around Huntsville yielded 1000 pounds of cotton per acre.

When Huntsville was occupied by Union forces in 1862, the Huntsville Depot was used as a prison for Confederate soldiers. Graffiti left by the soldiers can still be seen on the walls.

Huntsville was the birthplace of six Civil War generals--three on each side.

A product of the Army Ballistic Missile Agency (ABMA) at Redstone Arsenal in Huntsville, Alabama, the Redstone Rocket was designed as a surface-to-surface missile for the U.S. Army. It was named for the arsenal on 8 April 1952, which traced its name to the region's red rocks and soil.

With its mild climate, abundant streams, and chalky soil, north Alabama is ideal for growing watercress, and Huntsville was the largest producer of watercress in the world. Serving for serving, watercress contains more iron than spinach, more calcium than milk and three times the vitamin E as lettuce.

Huntsville's "Rocket City" nickname is thanks largely to Wernher von Braun and his team of fellow German-born rocketeers who settled there in the 1950s. In the years that followed, Huntsville, Redstone Arsenal and NASA's new Marshall Space Flight Center showed how seriously they took the Rocket City label with a string of successes that changed the world, producing the Jupiter rocket that answered the challenge of Sputnik by launching the first American satellite and the Redstone rocket that made Alan Shepard the first American astronaut in space.

The name Monte Sano is Spanish for "Mountain of health". This name comes from the fact that curative health resorts used to be located on the mountain to take advantage of the fresh air, clean water, and cooler temperatures.