John B. Henderson studied independently while working as a farm hand before teaching school and practicing law. He held positions in the Missouri House of Representatives and served in the U.S. Senate as a Unionist and later as a Radical Unionist. Henderson commanded federal forces in northeast Missouri during the Civil War and was active in Democratic politics, changing parties multiple times due to Missouri's political realignment. He returned to Washington, D.C. in the late 1880s and lived in Henderson Castle with his wife, Mary Foote Henderson.

John B. Henderson's political journey reveals an intriguing blend of moderate emancipation principles and strategic alliances with opposing factions. His shifting party affiliations during Missouri's political realignment showcase an ideologically agile approach. Henderson's military leadership and subsequent legislative alliances with Radicals highlight a calculated strategy to balance regional interests with broader political goals.