Toxic metals cause neurodegeneration via formation of toxic complexes with the cellular compounds and production of highly reactive oxygen species. The present study aimed to investigate the role of mitogen-activated protein kinase (MAPK) signaling pathway in iron, lead, and arsenic induced neurotoxicity. Also, to explore their effect on brain enzymes, inducible nitric oxide synthase (iNOS) and nuclear factor κB (NF-κB) in rat brains. Rats were divided into four groups (n = 8): Control group, lead group (30 mg/kg lead acetate), arsenic group (5 mg/kg sodium arsenite), and iron group (100 mg/kg ferric hydroxide). Treatments were given three times/week orally for 2 months. Brain tissues were assessed for reduced glutathione and malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), alkaline phosphatase (ALP), acid phosphatase (ACP), Na /K activated adenosine 5'-triphosphatase (Na /K -ATPase) and acetylcholinesterase (AChE) activities, expression of iNOS and NF-κB, and Western blot analysis of c-Jun NH(2)-terminal kinase (JNK) and extracellular signal-regulated protein kinase (ERK) proteins. Levels of arsenic, iron, and lead were significantly (p = 0.000) increased in blood and brain tissues. Levels of MDA, SOD, CAT, iNOS, and NF-κB gene expression, phosphorylated JNK and phosphorylated ERK proteins were increased significantly in lead, arsenic, and iron treated rat groups compared to control. ALP, ACP, AChE, and ATPase activities in brain were significantly altered in metal-treated rat groups compared to control. Iron, lead, and arsenic induced neurotoxicity activated the pro-inflammatory mediators NF-κB, iNOS, and MAPK pathway and altered the activity of brain ALP, ACP, Na /K -ATPase, CAT, SOD, and AChE.