<p><i>Paeonia lactiflora</i>, a member of the genus <i>Paeonia</i>, is a perennial herbaceous plant, and its roots have been utilized as herbal medicine in traditional Chinese medicine for over 2000&#xa0;years. <i>Paeonia lactiflora</i> shows therapeutic potential in autoimmune disorder, dermatological disorder, liver disorder, metabolic syndromes as well as disorders related to the heart and brain systems. The total glucosides of paeony serve as one of the fundamental components responsible for the pharmacological properties. Among the components of total paeony glucosides, paeoniflorin, a monoterpenoid glycoside, has demonstrated neuroprotective effects. Currently, paeoniflorin has been widely used in nervous system diseases, including depression, Alzheimer, Parkinson, neuropathic pain, etc. The related mechanisms of paeoniflorin on nervous system diseases are involved in anti-inflammatory, antioxidant, immune regulation and autophagy effects. Certain research of paeoniflorin on neuroprotective effects has attracted increasing attention, yet the specific mechanisms are still unclear. Hence, the review systematically elaborates on the neuroprotective effects of paeoniflorin. Although preclinical studies have confirmed the neuroprotective potential of paeoniflorin, its clinical transformation still faces challenges. Future research needs to focus on human clinical trials, solve its pharmacokinetic bottlenecks, and use multi-omics technology to reveal its mechanism of action. In addition, exploring the synergistic treatment strategy of paeoniflorin and existing drugs will provide a key direction for promoting its practical application.</p>