The aim of this study is to explore the ameliorative effects of α-lipoic acid (ALA) and/or Spirulina platensis (SP) against manganese (Mn)-induced brain damage. Sixty-four rats were classified into eight equal group, group I served as negative controls, group II received normal saline as a vehicle, group III treated with ALA (50 mg/kg/day), group IV treated with SP (300 mg/kg/day), group V treated with manganese chloride (MnCl2) at dosage of 74 mg/ kg/five times/week, along with rats in groups VI (MnCl2/ALA), group VII (MnCl2/SP) and group VIII (MnCl2/ ALA/SP). All treatments were administrated through oral route for eight-week, after that, the brain Mn, oxidant/ antioxidant stress and inflammatory biomarkers, as well as the histopathological and immunohistochemical changes of the brain tissues were examined. Our results revealed that MnCl2 induced an overwhelming neurotoxicity evident by the elevation of brain Mn, serum protein carbonyl, brain tumor necrosis factor-α with reduction in serum superoxide dismutase and brain interleukin-10. Histologically, Mn accumulation caused structural damage, intense brain caspase-3 immuno-expression and induction of heat shock protein-70. Administration of ALA and/or SP significantly decreased the brain levels of Mn, reduce the inflammatory response, re-established the cytotoxic changes and downregulated the caspase-3 immunoexpression of HSP-70. We can conclude that simultaneous ALA and/or SP administration elicited the most favorable protective effects against the Mn-induced neurotoxicity