Fighting in the European Theater, the division advanced through France and Germany through the end of the war, fending off heavy German counterattacks along the way.

Plans called for the division to include a headquarters, headquarters troop, the 199th Infantry Brigade (397th and 398th Infantry Regiments and 374th Machine Gun Battalion), 200th Infantry Brigade (399th and 400th Infantry Regiments and 375th Machine Gun Battalion), 373rd Machine Gun Battalion, 175th Field Artillery Brigade (373rd-375th Field Artillery Regiments and 25th Trench Mortar Battery), 325th Engineers, 625th Field Signal Battalion, and 325th Train Headquarters and Military Police (Ammunition, Engineer, Sanitary, and Supply Trains).

The 25th Trench Mortar Battery was formed at Camp Stanley, Texas, in August 1918 and was assigned to the 175th Field Artillery Brigade, but never ended up joining.

As the 1920s gave way to the 1930s and many World War I-experienced Reservists began to retire, the single largest cohort of the division's assigned officers became new ROTC (Reserve Officers' Training Corps) graduates chiefly from West Virginia University in Morgantown, the University of Kentucky in Lexington, or Western Kentucky State Teachers' College in Bowling Green.

The officer cadre (regimental, battalion, and company commanders) was designated by the end of August, and was dispatched to training schools to prepare them for their new assignments.

In mid-October, the non-commissioned officer cadre, provided principally by the 76th Infantry Division arrived at Fort Jackson.

Over 13,000 enlisted fillers, consisting of men from all across the United States, "salesmen from New York; farmers from the Carolinas, Georgia, and Alabama; mechanics from New Jersey; clerks from the New England states; mill workers from Pennsylvania and Delaware," arrived in short order thereafter.

[11] While at Fort Bragg, Technical Sergeant Walter L. Bull earned the first Expert Infantryman's Badge.

[11] Between January 1943 and August 1944, the division sent 14,636 enlisted men and 1,400 officers as cadres or fillers for other units or to overseas replacement depots.

In exchange, the division received men from replacement training centers (particularly starting in the summer, when demand for replacements in all theaters became so high that the centers, rather than units, again became the primary source of overseas replacements), the pared-down Army Specialized Training Program, aviation cadets returned to the ground forces, men from disbanded units in other branches of the Army (principally antiaircraft and tank destroyer), and men who had volunteered for the infantry from other branches of the Army.

[13] The attack jumped off on 12 November, and the division drove against the German Winter Line in the Vosges Mountains.

The division occupied the nearby areas of Wingen and Lemberg after fierce fighting on 6–10 December.

[13] On 14 December, regiments from the 100th started their assault on a minor fortification Freundenburg and Fort Schiesseck, a major defensive work in the region.

[13] The division was ordered to halt its attack and to hold defensive positions south of Bitche as part of the Seventh Army during the Battle of the Bulge.

After further attacks stalled and the Germans began to withdraw, the sector was generally quiet and the division prepared to resume its offensive east.

[17] Shifting to Göppingen on 30 April, the Division engaged in occupational duties as the war in Europe came to an end on V-E Day.

[18] 100th Infantry Division returned to the United States via the Hampton Roads Port of Embarkation on 10 January 1946, and was released from active duty at Camp Patrick Henry, Virginia that day.

Its mission became to teach basic, advanced, and common training skills to soldiers from the Army's active, reserve, and National Guard components.

[7] In 1961, some 1,500 soldiers from the 100th were activated and sent to Fort Chaffee, Arkansas,[7] in order to provide support during the Berlin Crisis.

During their time on active duty, the 100th successfully trained some 32,000 soldiers after thoroughly rebuilding and fixing the old Army base.

[20] The 928th Field Artillery Battalion became the 2nd Brigade, 100th Division responsible for armored cavalry unit training.

[11] By 1986, it was the largest reserve unit within the state of Kentucky, commanding fifty-eight percent of instate reservists.

[11] In 1995 the division was reorganized to include Army Reserve schools, taking over the responsibilities for new programs.

In 1996 the 100th Division's 1st Brigade worked with Readiness Group Knox to pioneer the national training experiment to reserve combat units at crew and platoon levels.

[3] During 1997, the division was tasked with partial responsibility for Operation Future Challenge at Fort Knox, a six-week Reserve Officer's Training Corps Basic Camp during each summer.

[11] By 2006, the division had moved its headquarters from Louisville to Fort Knox, easing distance strains in administration and training.