The biochemical, oxidative DNA damage, and the histological alterations associated with thiamethoxam (MX) exposure, a second-generation neonicotinoid broadly used in Egyptian agriculture, were assessed. Also, the role of N-acetylcysteine (NAC), (150 mg/kg/ day) on the adverse effect of MX was investigated. Rats were orally preserved with a sub-lethal dose (1/50 LD 50 ) of MX at 31.26 mg/kg/day, five doses/week for 28 days. The MX exposure resulted in a significant decrease in rats' body weight, protein concentration of both serum and urine, sera catalase (CAT), and glutathione peroxidase (GPx) activities compared to control. In addition increase in sera creatinine, urea, bilirubin, alkaline phosphatase (ALP), superoxide dismutase (SOD), and malondialdehyde (MDA) levels were observed. While the assessment of DNA damage revealed significant altitude in 8-hydroxy-2'-deoxyguanosine (8-OH-2DG) levels in both serum and urine samples. The present findings were supported by microscopic observation of liver and kidney tissues. Evidently, thiamethoxam can damage liver and kidney functions impaired the DNA, and cause histoarchitecture lesions in rats at the tested sublethal dose. In addition, NAC supplementation significantly attenuated of MX adverse effect which reflects its protective influence against MXinduced hepatic-nephrotoxicity.