When the National Socialists came to power, Wiesbaden once again became a military base: In October 1936, the General Command of the XII. Army Corps and the third battalion of the Infantry Regiment 38 moved into Wiesbaden. The "Ochamps Barracks" were inaugurated on the former parade ground on Schiersteiner Straße in December 1937. Other barracks, such as the Reduit, were also reactivated and expanded to accommodate new units. In 1936, the Luftwaffe expanded Erbenheim Airport into an airbase. Shortly after coming to power in 1933, the regime began preparations for a future air war.

A central organization office for civil air protection was set up at Dotzheimer Straße 24. Shortly after the invasion of Poland, in addition to a deep bunker, a high bunker was built at the springs on Kaiser-Friedrich-Platz and the tunnel system converted into a bunker on Coulinstraße in today's Friedrich-Ebert-Allee 8 on the site of a sports field. In May 1940, another temporary air-raid shelter with space for 1,400 people was built in the immediate vicinity of the Kurhaus. In the course of mobilization, most of the school buildings were confiscated and sports halls were converted into storage facilities for food; between 1941-44, regular lessons were only possible with great effort.

Municipal hospital and welfare facilities were converted into military hospitals or for the care of the war-wounded. At the beginning of the war, the War Damage Office was set up, which became the Wehrmacht and War Damage Office in 1942. At times, the large hotels were used entirely by the military and its administration. Fundraising campaigns for the Wehrmacht and social institutions such as the Red Cross were intended to help finance the war and the associated expenses. The 60-hour working week was not introduced until September 1944.

In order to ensure supplies for the residents and prevent shortages as in the First World War, the administration issued ration cards on 28.08.1939 and reorganized the procurement of fuel. The second rationing period began on September 24th, in which further consumer goods were regulated with bread and soap cards. In November, clothing cards were introduced and the production of sausage, ham and tinned meat was stopped in order to secure the meat supply. The ration remained consistently high at over 2,000 kilocalories per inhabitant per day until 1944. Cultural events at the state theater and the spa orchestra were also maintained until the end of 1944. Since 1944, however, only potatoes were allowed to be grown in the gardens. In September, the weekly bread ration was reduced by 200 g.

During the first two years of the war, there were hardly any shortages in the supply of fuel, as the demand could be covered by the company's own reserves and the exploitation of the occupied territories. The shortage of coal until 1944 due to rationing was compensated for by extensive savings measures, in which the residents were trained by the city administration. It was not until the fall of 1944 that the city administration decided to start logging. Road by road, the foresters allocated trees to the citizens to replace the lack of coal with wood.

Bus transportation became more difficult from year to year. Among other things, buses ran on town gas, which was stored in containers on the roof of the vehicle; women were employed as conductors to keep the service running. From 1944 onwards, the increasing bombing meant that regular local public transport as in peacetime was no longer an option. The first restrictions on long-distance services were imposed from June 1944 due to the cancellation of D and express trains.

The hostilities of the war did not leave Wiesbaden unscathed; between August 1940 and March 1945, the city was attacked by Allied bombers on 66 days. On November 29, 1940, the first air strikes were reported on the banks of the Rhine, Erbenheimer Strasse and the Army Production Office in Kastel. The first casualties were reported after an air raid on Fritz-Kalle-Straße on 06.05.1941. The bombs that fell on 12.08.1942 hit various Wehrmacht facilities as well as the Glyco-Metallwerke production plant. The first major attack on Wiesbaden took place on 17.09.1942, hitting the Dyckerhoff und Söhne cement works, among others. It was not until October 4, 1943 that American units took part in the air raids. From January to August 1944, there were more frequent attacks on both industrial and residential areas.

The period from September 1944 until the liberation of the city is regarded as the actual bombing war in which numerous citizens lost their lives. On September 13, 1944, there was a massive attack on the railroad tracks, which considerably restricted rail traffic. Six days later, the Kalle chemical works, the Albert chemical factory and the Dyckerhoff cement works, among others, were devastatingly hit. 50 people fell victim to this attack. As a result of the material destruction, cement production fell by 50%. On December 4, 1944, the site of Wiesbaden-Ost station was so badly destroyed that rail operations had to be suspended for a week. In the period that followed, the higher SS and police leadership moved their offices out of the city to safe alternative quarters on the edge of the forest, which had been set up by prisoners from the Hinzert SS special camp. A total of 1,479 air victims are recorded from the heavy raids on February 8 and July 28, 1944.

Around 18% of the housing in Wiesbaden, Kastel, Amöneburg and Kostheim was destroyed. The heaviest bombing raid in the night from February 2 to 3, 1945 claimed 570 lives and 28,000 residents lost their homes. The spa district was particularly badly hit. The Paulinenschlösschen, the Kurpark, the Kurhaus and the theater, the Hotel Vier Jahreszeiten, the Marktkirche, the city palace, the town hall and the police headquarters were severely damaged. The water, gas and electricity lines had not yet been fully repaired by October 1945. The direct hit of an air mine into the lyceum next to the market church on Schlossplatz and the subsequent collapse proved to be a deadly trap for many Wiesbaden residents who had been using the massive building as an air raid shelter. Biebrich Palace also suffered severe damage shortly before the end of the war. The Platte hunting lodge was deliberately destroyed in February 1945, as an anti-aircraft position was stationed there. In addition to these Allied hits, there were also a few German aircraft shot down by attacking aircraft. On 08.11.1944, a US fighter bomber was shot down by the Wiesbaden air defense. The pilot was able to save himself by parachute and was eventually arrested. Another US Air Force pilot who was shot down fell victim to the vigilante justice of an angry crowd in Delkenheim on December 30, 1944. By the end of the war, around 30% of Wiesbaden's buildings had been destroyed.

On March 28, 1945, the Second World War ended for Wiesbaden with the invasion of American troops. The last city commander Colonel Wilhelm Karl Zierenberg and the remaining administrative officials Fritz Reeg, Christian Bücher and Dr. Carl Stempelmann defied the so-called Nero Order issued by Gauleiter Jacob Sprenger and Lord Mayor Felix Piékarski, who had called for the evacuation of the city and the destruction of its infrastructure shortly before fleeing Wiesbaden on March 25. This prevented further destruction and dismantling. The First Alderman and City Treasurer Dr. Gustav Heß handed the city over to the Americans against the orders of the military and the party. As a sign of peaceful surrender, the white flag was hoisted on the bunker at the museum on March 28, 1945 at 5:45 am.