Neurodegeneration is an elucidating feature of many neuronal disorders including Alzheimer’s, disease, Parkinson’s disease, and cerebral ischemia. These neurodegenerative disorders are a major public health concern with high mortality and morbidity rates around the world. Presently, researchers have concentrated their efforts on determining the neuroprotective activity of natural products for the management of neurological manifestation associated with neurodegeneration or aging. Silibinin, an active component of the plant Silybum marianum (family: Asteraceae) was used for the treatment of liver diseases from ancient times. Recently several preclinical studies provide supportive evidence for the neuroprotective activity of silibinin in experimental animals. Besides its antioxidant effect, silibinin exhibits neuroprotective activities by altering several cellular and molecular signaling pathways like BDNF, ER/PI3/Akt, NfκB, JNK, IR & IGF-IR, mTOR, and many more against brain-related neurotoxicity. This review provided a comprehensive summary of the chemistry, pharmacokinetics, side effects, and pharmacological effects of silibinin against various neurodegenerative disorders with a prominent cellular and molecular mechanism. The literature reviews and preclinical studies demonstrated that silibinin could be an alternate candidate for the management of neurodegenerative disorders. Thus, there is a scope for further preclinical and clinical research to introduce this phytoconstituent as a therapeutic alternative candidate.