Neurodegenerative diseases are major global health concerns due to progressive neuronal deterioration. Natural compounds, particularly plant polyphenols, are being explored for their neuroprotective potential. O. sanctum (Holy Basil or Tulsi) polyphenols, which possess pharmacological activities, were emphasized in this review. O. sanctum contains flavonoids, phenolic acids, and tannins, which exhibit strong antioxidant activity through scavenging free radicals and boosting endogenous antioxidants. These compounds also demonstrate anti-inflammatory activities, modulate cytokine production, and increase synaptic plasticity. Their anti-apoptotic effects inhibit the degeneration of neuronal cells. Preclinical studies demonstrated potential neuroprotective effects of O. sanctum polyphenols in different NDD models, with a few clinical studies suggesting their safety and efficacy over conventional neuroprotective medicines. Elucidating these mechanisms could help the development of O. sanctum polyphenols as drugs to combat NDDs and improve patient outcomes.