Currently, much emphasis is being laid on understanding the role of nutrition to alleviate neurodegenerative conditions. Here we employed a Drosophila model to test the hypothesis that Whey protein isolate (WPI) enrichment can attenuate Manganese (Mn) induced locomotor phenotype, oxidative stress and neurotoxicity. Mn exposure (0–30mM) to young (8–10d old) males/females and aged (30–35d old) males elicited a concentration-dependent temporal mortality and locomotor deficits. In general, females and aged males were more susceptible than young males. Mn exposure (5–15mM, 5d) among male flies, besides induction of oxidative stress (elevated levels of MDA and protein carbonyls with a concomitant decrease in glutathione levels), caused significant perturbations in the activities of antioxidant enzymes and mitochondrial complexes. In the co-exposure paradigm, WPI fortification (0.25–0.5%) markedly ameliorated Mn-induced locomotor phenotype, mortality, oxidative stress and restored the activity of the antioxidant enzymes, cholinergic function, and dopamine levels. In a satellite study, flies given prophylactic treatment (10d) with WPI were more resistant(evidenced by a lower incidence of mortality and locomotor deficits) to an acute MPP⁺ challenge suggesting its potential to enhance survival pathways. Collectively, these data suggest the potential of WPI enrichment to attenuate Mn-induced toxic manifestations in the Drosophila model. Based on these findings, we propose that fortification of diet with WPI offers a useful approach to alleviate Mn-induced toxic manifestations and neuronal dysfunctions in humans, especially in occupational settings.