The present study was conducted to investigate the protective effects of N-Acetyl-L-cysteine (NAC) and S-methyl- L-cysteine (SMC) against hepatic oxidative stress and brain damage induced by acetamiprid (ACP) in rats, which were evaluated by histopathological changes, measuring serum biomarkers and antioxidant defense systems. In this study, 42 rats were randomly divided into 6 groups and administered by intraperitoneally for one week: the control group, the sham group (normal saline), ACP alone (5 mg/kg) (group1), NAC alone (160 mg/kg) (group2), ACP + SMC (100 mg/kg) (group3), ACP + NAC (group 4) and ACP + NAC + SMC (group 5). Our results showed that acetamiprid induces liver injures including infiltration of inflammatory cells, congestion and altered histo-architecture and brain damages including gliosis, hyperemia and necrosis. The biochemical analyses showed that acetamiprid significantly altered the structural and biochemical profiles of liver which may be due to the loss of integrity of cell membranes. Furthermore, antioxidant parameters results of ACP group revealed that glutathione (GSH) and total antioxidant capacity (TAC) levels decreased significantly, while lipid peroxidation (LPO) content and glutathione-S-transferase (GST) and catalase (CAT) activities increased in both tissues (P < 0.05), suggesting tissue oxidative damage, which was also confirmed histopathological. Conversely, administration of NAC and SMC ameliorated LPO, GSH content and antioxidant enzymes system considerably (P < 0.05) in both tissues. Moreover, NAC and SMC administration also improved liver and brain malfunction. These results indicate that both NAC and in to a lesser amount SMC have a potent antioxidant protection in both tissues of rat against ACP-induced oxidative stress.