One of the most advantageous natural substances is curcumin, a major metabolite of Curcuma longa (turmeric), which has pharmacological characteristics.  On the other hand, curcumin's low bioavailability has long prevented its use in medicine.  Over the past few years, curcumin metabolites have attracted a lot of research attention, and extensive studies have been conducted to improve curcumin use.  Moreover, mounting evidence suggests that the biological activity of curcumin or its metabolites is on par with or superior to that of curcumin's precursor.  Tetrahydrocurcumin, a significant curcumin metabolite, has received a lot of attention recently for its protective properties.  The potential neuroprotective mechanisms of Tetrahydrocurcumin were elucidated and validated using both in vitro and in-silico investigations.  To demonstrate the effect of Tetrahydrocurcumin on the hippocampal and dopaminergic neuron viability, HT-22 (hippocampal neurons) and N27 (dopaminergic neurons) were utilized.  Additionally, markers for oxidative stress, mitochondrial function, inflammation, and apoptosis were investigated in order to better understand the neuroprotective mechanisms.  Both dopaminergic and hippocampal neurons were significantly protected by tetrahydrocurcumin.  Its antioxidant and anti-apoptotic properties were considered to be responsible for the neuroprotection.  RNA sequencing was performed as well to confirm the neuroprotective benefits.  In order to prevent, reduce the rate of progression, and treat neurodegenerative pathologies, tetrahydrocurcumin can be an effective therapeutic natural bioactive metabolite.