The 151st Infantry Regiment traces its roots to the Indiana Territory Indiana Rangers militia. It was in the 1811 Battle of Tippecanoe that it earned its motto "Wide Awake! Wide Awake!" In 1846, the 2d Regiment, Indiana Volunteers, Indiana Brigade was mustered into Federal Service for the Mexican–American War, and was again federalized in 1861 during the American Civil War. It was reorganized in 1882 into the Indiana Legion, which was renamed the Indiana National Guard 5 March 1895. The 151st Infantry Regiment is credited with 24 campaigns from the Civil War due to lineage traced to the 7th, 10th, and 11th Indiana Volunteer Infantry Regiments.

The Regiment was again federalized in 1898 for service in the Spanish–American War. In 1900, it was reorganized as the First Infantry, Indiana National Guard. The First Infantry was mustered into federal service at Fort Benjamin Harrison in 1916 for service in the Mexican Border Campaign.

With the outbreak of World War I, the First Infantry was reorganized into the 151st Infantry Regiment, and assigned to the 76th Infantry Brigade, 38th Division. The division was mobilized for Federal service in 1917 and demobilized in 1919. The division was again activated in 1941 in preparation for World War II. In the South Pacific, the 151st Regiment earned three battle streamers (New Guinea, Leyte and Luzon) helping the 38th Infantry Division win the nickname "Avengers of Bataan."