Abstract: Zhishi Xiebai Guizhi Decoction (ZXGD) is one of the first hundred classic prescriptions published by the National Administration of Traditional Chinese Medicine. A systematic review was conducted on the historical origin, development, understanding, and clinical application of this formula. ZXGD is scattered in the works of medical experts during the Jin and Tang dynasties, but there is a confusion in the name and composition of the prescription. From the Wei and Jin dynasties to the Tang and Song dynasties, the understanding and application of ZXGD mainly focused on discussing the two pathogens of wind and cold; during the Jin and Yuan dynasties, there was a breakthrough in the argument towards internal causes of chest pain; after the Ming and Qing dynasties, the understanding and application of this decoction were mostly based on the theory of qi inversion disorder. Since modern times, the application of ZXGD has expanded to 17 diseases, involving multiple systemic diseases such as the circulatory system, digestive system, and respiratory system diseases. The main treatment is angina in circulatory system diseases, followed by myocardial infarction and myocardial ischemia.