Benjamin O'Fallon (1793–1842) was an Indian agent along the upper areas of the Mississippi and Missouri Rivers. He interacted with Native Americans as a trader and Indian agent. He was against British trappers and traders operating in the United States and territories. He believed that the military should have taken a strong stance against the British and firm in negotiations with Native Americans. Despite his brash manner and contention with the military, he was able to negotiate treaties between native and white Americans. In his early and later careers, he built gristmills, was a retailer, and a planter. He collected Native American artifacts and paintings of tribe members by George Catlin. His uncle William Clark was his guardian and financial backer.

Benjamin O'Fallon was born on September 20, 1793, in Lexington, Kentucky. His parents were James O'Fallon, an Irish immigrant, and Frances "Fanny" Clark O'Fallon, the sister of William and George Rogers Clark. James came to the American colonies in 1774 from Ireland. During the American Revolutionary War, he served in George Washington's army as a surgeon. After the war, he was a general agent for the South Carolina Yazoo Land Company in 1789. He sought business schemes in St. Louis with adventurers, French agents, and Spanish officials, like Edmond-Charles Genêt (Citizen Genêt), George Rogers Clark and General James Wilkinson.

In 1791, he married Frances Eleanor Clark (1773–1825) in Kentucky, with whom they had two sons John and Benjamin. James died a few months after Benjamin's birth. By that time, the couple had separated. Frances married for a second time to Captain Charles Mynn Thruston in 1796, with whom they had two sons, Charles and William. Thruston died and in 1805 she married Judge Dennis Fitzhugh.

William and George Clark became involved in the O'Fallon and Thruston boys' lives after the death of Captain Thruston. William was their guardian in 1808 and a year later William brought Benjamin and John to St. Louis, where he was an Indian agent. At some point, the four boys lived at Mulberry Hill and then Clark's Point, in Louisville, Kentucky. The Clarks were slave-owners. Beginning in his childhood, O'Fallon had chronic health problems of his bowels, spleen, and liver. He was ill-mannered.

Fanny lived in Louisville, Kentucky until April 1825. She came to St. Louis to be under the care of Dr. Bernard G. Farrar, her son-in-law. She died on June 19, 1825, and was buried at the Bellefontaine Cemetery in St. Louis.

He established a business selling meat and flour in 1813 with James Kennerly, who was the brother of William Clark's second wife and cousin of his first wife. A year later, O'Fallon supplied Clark's military expedition to Prairie du Chien in present Wisconsin. He built gristmills and sawmills north of St. Louis in 1815, but sold the mills after one year.

O'Fallon was a partner of the Missouri Fur Company. In 1816, O'Fallon became a trader and special agent for the Sioux and other tribes on the upper Mississippi River. In 1818, he was appointed as a subagent for the upper Missouri River. At Prairie du Chien, O'Fallon kept track of British traders and their relationships with Native Americans. O’Fallon said, "It will be a vain struggle to attempt the change of the treacherous savage, so long as un-principled British Traders are permitted to trade within our Territory."

In 1818, O'Fallon took British trader Robert Dickson in custody, put him in shackles, and took him to St. Louis. O'Fallon declared that he was trading illegally on American territory and considered him the most treacherous of the British traders for provoking Native Americans against Americans. At St. Louis, he turned him over to his uncle William Clark (then the governor of Missouri Territory), who released Dickson and had him returned to Canada.