Medicinal plants and their phytochemicals have been extensively employed worldwide for centuries to address a diverse range of ailments, boasting a history that spans several decades. These plants are considered the source of numerous medicinal compounds. For instance, silymarin is a polyphenolic flavonoid extract obtained from the milk thistle plant or Silybum marianum which has been shown to have significant neuroprotective effects and great therapeutic benefits. Neurodegenerative diseases (NDs) are a class of neurological diseases that have become more prevalent in recent years, and although treatment is available, there is no complete cure developed yet. Silymarin utilizes a range of molecular mechanisms, including modulation of MAPK, AMPK, NF-κB, mTOR, and PI3K/Akt pathways, along with various receptors, enzymes, and growth factors. These mechanisms collectively contribute to its protective effects against NDs such as Alzheimer's disease, Parkinson's disease, and depression. Despite its safety and efficacy, silymarin faces challenges related to bioavailability and aqueous solubility, hindering its development as a clinical drug. This review highlights the molecular mechanisms underlying silymarin's neuroprotective effects, suggesting its potential as a promising therapeutic strategy for NDs.