The second 38th Infantry was first established on 28 July 1866, as part of the Regular Army, one of six segregated, all-black regiments created following the Civil War.

It was organized on 1 October of that year at Jefferson Barracks, Missouri, and was stationed in New Mexico Territory and along the transcontinental railroads then under construction.

The current 38th Infantry Regiment was constituted in the Regular Army on 15 May 1917, and was organized on 1 June 1917 at Syracuse, New York.

The regiment arrived at the port of New York on 20 August 1919 on the troopship USS Matsonia and was transferred the same day to Camp Merritt, New Jersey, where emergency period personnel were discharged from the service.

In April 1933, the regiment assumed command and control of the Fort Douglas Civilian Conservation Corps District.