In 1808 Regular Army was reorganized to meet the growing threat posed by the Indian nations living on the western boundaries of the United States. The first permanent Regular Army unit to bear the designation of 4th Infantry Regiment was constituted on 12 April 1808 in the Regular Army, and organized during May–June 1808 in New England.
Under the leadership of General William H. Harrison, the 4th Infantry, commanded by Colonel John Parker Boyd, was sent into the Northwest Territories, which included Ohio, Indiana, and Illinois. Its mission was to eliminate the threat posed by a union of Indian tribes from the surrounding area. The hostile actions of these tribes were effectively stopping settlement of this vast area. General Harrison, who was later to become a United States President, led the 4th Infantry and a force of militia and volunteers against the Indians at Tippecanoe. During this battle, the American forces completely routed the Indians, bringing peace to the area, but at a cost of 188 dead. The regiment then returned to Fort Vinncennes, and in 1812, after a trying march through the forests of Ohio, joined forces with General William Hull.