Panax notoginseng (P. notoginseng) is a well-known and commonly used Chinese herbal medicine in Asian countries. As one of the major species in the Panax genus, it has a distinct chemical composition and medical application compared with other species. P. notoginseng attracts attention and interest due to its potential therapeutic effects not only on blood diseases, but also other kinds of human chronic disorders. This paper critically reviewed the latest advance of knowledge on the pharmacological effects of P. notoginseng on a variety of chronic diseases including inflammatory bowel disease, arthritis, ischemia, atherosclerosis, Alzheimer disease and trauma, as well as hyperlipidemia, diabetes, and so on. As inflammation is considered the fundamental factor involved in the pathogenesis of chronic diseases, our review therefore focuses on understanding the involvement of classical inflammatory pathways underlying the mechanism of action of P. notoginseng. Potential clinical application was also discussed. Furthermore, by combining with network pharmacology, we introduced the major bioactive components of P. notoginseng, analyzed their cellular targets and associated signaling pathways. In conclusion, this review identified inflammatory pathway as the key signaling for determining the efficacy of P. notoginseng on chronic diseases. It is speculated that P. notoginseng is a multi-targeted agent with an anti-inflammatory property in the adjuvant and alternative treatment of human chronic diseases.