Initial production Panthers had a face-hardened glacis plate (the main front hull armor piece), but as armor-piercing capped rounds became the standard in all armies (thus defeating the benefits of face-hardening, which caused uncapped rounds to shatter), this requirement was deleted on March 30, 1943. By August 1943, Panthers were being built only with a homogeneous steel glacis plate. The front hull had 80 mm of armor angled at 55 degrees from the vertical, welded but also interlocked for strength. The combination of well-sloped and thick armor meant that few Allied or Soviet weapons could penetrate this part of the tank.

The armor for the side hull and superstructure (the side sponsons) was much thinner (40–50 mm). The thinner side armor was necessary to keep the overall weight within reasonable bounds, but it made the Panther vulnerable to attacks from the side by most Allied and Soviet tank and anti-tank guns. German tactical doctrine for the use of the Panther thus emphasized the importance of flank protection. Five millimeter thick skirt armor, known as Schürzen, intended to provide protection for the lower side hull from Soviet anti-tank rifle fire was fitted on the hull side. Zimmerit coating against magnetic mines started to be applied at the factory on late Ausf D models beginning in September 1943; an order for field units to apply Zimmerit to older versions of the Panther was issued in November 1943. In September 1944, orders to stop all application of Zimmerit were issued, based on rumors that hits on the Zimmerit had caused vehicle fires.

Panther crews were aware of the weak side armor and made unauthorized augmentations by hanging track links or spare roadwheels onto the turret and/or the hull sides. The rear hull top armor was only 16 mm thick, and had two radiator fans and four air intake louvres over the engine compartment that were vulnerable to strafing by aircraft.

As the war progressed, Germany was forced to reduce or no longer use certain critical alloy materials in the production of armor plate, such as nickel, tungsten, molybdenum, and manganese; this did result in lower impact resistance levels compared to earlier armor. Manganese from mines in the Ukraine ceased when the German Army lost control of this territory in February 1944. Allied bombers struck the Knabe mine in Norway and stopped a key source of molybdenum; other supplies from Finland and Japan were also cut off. The loss of molybdenum, and its replacement with other substitutes to maintain hardness, as well as a general loss of quality control resulted in an increased brittleness in German armor plate, which developed a tendency to fracture when struck with a shell. Testing by U.S. Army officers in August 1944 in Isigny, France showed catastrophic cracking of the armor plate on two out of three Panthers examined

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