Discovering effective agents to slow or stop neurodegeneration is a challenging task. Over decades, only a few drugs were approved by Food and Drug Administration (FDA) and most ended in failure. The lessons learned have switched the strategy of drug discovery from designing highly selective ligands to a network pharmacology approach. This enables many natural products like butylphthalide (NBP) once again to be regarded as a valuable source of leads for drug discovery. In this review, we first start with the neuroprotective effects of NBPs on acute ischemic stroke, and later spread to their applications in major neurodegenerative diseases. The underlying mechanisms are also discussed in order to provide a direction for further study. Hopefully, this review could bring some new insights for drug development in this struggling field.