“Zhusha Anshen Wan is a classic prescription derived from Li Dongyuan's "On the Diagnosis and Confusion of Internal and External Injuries" during the Jin and Yuan dynasties. It is composed of five traditional Chinese medicines: Zhusha, Huanglian, Danggui, Shengdihuang, and Licorice. Under the guidance of traditional Chinese medicine theory, this formula is used to treat insomnia, palpitations, anxiety and other restless diseases caused by excessive heart fire and insufficient yin blood, and has auxiliary anticonvulsant effects on epilepsy and other diseases. However, the potential nerve, liver, and kidney damage, as well as the risk of accumulation in the body, of its flagship drug cinnabar (mainly composed of mercury sulfide (HgS)) have caused controversy in its clinical application, and it has not yet been officially included in the Pharmacopoeia of the People's Republic of China. In addition, due to the restrictions of the Minamata Convention on Mercury, natural medicinal cinnabar resources are increasingly scarce, making the evaluation of the efficacy and safety of synthetic cinnabar particularly urgent. This contradiction highlights the complexity of traditional drug safety evaluation. Existing studies have shown that Zhusha Anshen Wan has definite pharmacological activity in calming the mind, improving sleep, and regulating emotional disorders. Other medicinal flavors in the formula may have antagonistic effects on the toxicity of Zhusha. Reports of severe mercury poisoning caused by standardized use of this formula in clinical practice are extremely rare. Research suggests that other medicinal flavors in the compound, such as Rehmannia glutinosa, Coptis chinensis, and Glycyrrhiza uralensis, may effectively reduce the liver and kidney damage of cinnabar by regulating gut microbiota, forming mercury complexes, and directly protecting target organs. The purpose of this article is to systematically review the pharmacological research progress of Zhusha Anshen Wan, deeply explore its mechanism of action, distinguish the toxicokinetic characteristics, safety risks, and scientific connotations of compound compatibility for reducing toxicity and enhancing efficacy of Zhusha Anshen Wan, and compare it with other commonly used Anshen drugs, in order to provide scientific basis and forward-looking thinking for the safe, rational application and deep development of Zhusha Anshen Wan in the modern context, emphasizing the important value of holistic research on traditional Chinese medicine formulas in solving the challenge of single component toxicity.”