Dietary fat modulates neuronal health and contributes to age-related nervous system disorders. However, the complex interaction between dietary fat and supplementation and its consequences on neurotoxic pathophysiology has been sparsely explored. The indigenous Alaskan bog blueberry (BB), Vaccinum uliginosum, is known to have anti-inflammatory properties, mostly attributed to its rich polyphenolic content. Here, we evaluate the interplay between dietary fat and BB supplementation on sub-chronic manganese (Mn) exposure that inflicts neurotoxicity and behavioral impairments. In both low-fat and normal-fat diets, BB supplementation attenuated the behavioral and the molecular hallmarks of Mn-induced neurotoxicity. On the contrary, a high-fat *