Due to global population aging and modern lifestyle changes, the incidence of central nervous system (CNS) disorders, such as neurodegenerative diseases, neuropsychiatric disorders, and cerebrovascular diseases, is increasing and has become a major public health challenge. Current medications commonly used in the clinic are far from satisfactory and may cause serious side effects. Therefore, the identification of novel drugs for the effective management of CNS diseases is very urgent. Puerarin, a highly bio active ingredient isolated from Pueraria lobata, is known to possess a broad spectrum of pharmacological properties including anti-diabetic, anti-inflammatory, anti-antioxidant, neuroprotective, and cardioprotective features. However, its clinical application is limited due to its poor water solubility. Since puerarin has demonstrated a wide range of neuroprotective functions in various CNS diseases, such as Alzheimer's disease, Parkinson's disease, cerebral ischemia, depression, and spinal cord injury, it has been attracting increasingly intense attention worldwide. In this review, we intend to extensively summarize the research progress on neuroprotective mechanisms of puerarin in recent years and discuss the future directions of its application in CNS disease treatment.