The British indeed used the fighting power of Native Americans in the War of 1812. William Henry Harrison fought the Shawnee nation at the Battle of Tippecanoe while Andrew Jackson commanded the Tennessee militia winning the Battle of Horseshoe Bend. The Treaty of Fort Jackson in 1814 signaled the end of Native American supremacy in Mississippi.

Following the war, Native Americans were moved to lands west of Mississippi, commonly referred to as “Indian Territory.” Although removal had gone on since the early 1800s, the Indian Removal Act of 1830, implemented during Andrew Jackson's presidency, resulted in the uprooting of entire tribes from their homelands

As some Native Americans refused to resettle, several smaller wars or skirmishes ensued. The Black Hawk War in Illinois and Wisconsin was one of these, ending in 1832. Attempts by the Cherokees to stop the removal brought them to the Supreme Court. In Cherokee Nation v. Georgia (1831), the Supreme Court ruled that the Cherokees could remain on their land and in Worcester v. Georgia (1832) the Supreme Court once again backed the rights of the Cherokees. Andrew Jackson refused to enforce the Court's decision. Although impeachment proceedings were started in the House of Representatives, they failed to go very far. From 1835 to 1838 the forced march known as the Trail of Tears resulted in the deaths of thousands of Cherokees.

The remaining Creek were uprooted from Mississippi and Alabama, and the Seminole fought to resist the U.S. Army's attempts to force their retreat from Florida. By the end of the 1850s, only scattered groups of Native Americans remained in the eastern United States.