ETHNOPHARMACOLOGICAL RELEVANCE: Neurodegenerative diseases (NDs) is a time-dependent course for a sequence of conditions that primarily impact the neurons in the human brain, ultimately, resulting in persistence and progressive degeneration and / or death of nerve cells and reduction of cognition and memory function. Currently, there are no therapeutic approaches to cure neurodegeneration, except certain medicines that temporarily alleviate symptoms, facilitating the improvement of a patients' quality of life. Danggui-shaoyao-san (DSS), as a famous Chinese herbal formula, has been widely used in the treatment of various illnesses, including neurodegenerative diseases. Although well-practiced in clinical medicine, the mechanisms involved in DSS for the treatment of neurodegenerative diseases remain elusive. MATERIALS AND METHODS: In the present study, a novel systems pharmacology approach was developed to decipher the potential mechanism between DSS and neurodegenerative disorders, implicated in oral bioavailability screening, drug-likeness assessment, target identification and network analysis. RESULTS: Based on a comprehensive systems approach, active compounds of DSS, relevant potential targets and targets associated with diseases were predicted. Active compounds, targets and diseases were used to construct biological networks, such as, compound-target interactions and target-disease networks, to decipher the mechanisms of DSS to address NDs. CONCLUSIONS: Overall, a well-understood picture of DSS, hallmarked by multiple herbs-compounds-targets-pathway-cooperation networks for the treatment of NDs, was revealed. Notably, this systems pharmacology approach provided a novel in silico approach for the development paradigm of traditional Chinese medicine (TCM) and the generation of new strategies for the management of NDs.