Moses Bates first surveyed the junction of Bear Creek and the Mississippi River north of St. Louis in 1818, and a cabin was built. By the 1830 census only 30 people were recorded living in the broad valley between Lover's Leap and Cardiff Hill, and the land titles were not clear. Finally, in 1837 the town of Hannibal was incorporated. By 1840 the census showed 1034 residents, including the Clemens family, whose son Samuel would grow up to be the famous author, Mark Twain.

In 1845 the town became incorporated as a "city," and by the 1850 census 2020 people called Hannibal home. The next 10 years would see the population triple as waves of immigrants made their way west. Many came from Ireland, including widower John Tobin with his young daughter Kate. His name was among the 1860 census listing 6505 inhabitants.

But the real boom came with the railroads. In 1859, the Hannibal-St. Joseph line was completed linking the Mississippi with America's West. It was this railroad that brought the letters to the famous Pony Express, which in turn carried mail all the way to California. In 1860 Hannibal was Missouri's third largest city, only exceeded by St. Jo and St. Louis. The railroad turned Hannibal into a major industrial city. Lumber floated down river from the forests of Wisconsin and Minnesota was brought ashore and milled by Hannibal's "lumber barons." Tobacco was a major crop and at one point Hannibal had twelve factories devoted to processing cigars and bulk tobacco.

This golden era of prosperity lasted for about 40 years. The city continued to grow through the turn of the century peaking at around 20,000 citizens. Then the river traffic declined along with the lumber industry. One hundred years after being the third largest city in Missouri, it had dropped to 18th by 1960. Its current population stands around 18,000.