In a previous study, we demonstrated the ability of papaya epicarp extract (PEE) to protect against oxidative stress-induced insult in human SH-SY5Y neuronal cells in a mechanism that appeared to be by means of PEE potent antioxidant properties. To further understand this relationship, we examined the effect of PEE intervention on aluminum (Al)-induced cytotoxicity in SH-SY5Y cells. The results indicated that PEE was effective in protecting against Al-induced cell death in a dose-dependent manner. PEE restored the Al-induced inhibition of folate-dependent methionine synthase activity and the antioxidant enzymes (catalase, glutathione peroxidases and superoxide dismutase). PEE ameliorated the Al-induced impairment of intracellular glutathione and total antioxidant capacity. Together, these findings indicate that PEE supplementation can play a neuroprotective role in ameliorating the changes in redox status of SH-SY5Y cells exposed to Al, a well-known environmental toxin that is involved in the pathogenesis of neurodegenerative diseases and neurodevelopmental disorders.