AbstractAluminum oxide nanoparticles (Al₂O₃‐NPs) are exceedingly used in various industrial and commercial applications, providing growing concerns about their potential adverse impacts on animals and human health. Therefore, the present study was conducted to evaluate the potential protective effect of sesamol (SML) against the induced hepatorenal toxicity of Al₂O₃‐NPs. Forty male rats were randomly assigned into four groups and treated orally for 28 consecutive days. Control group received distilled water. SML group received SML (100 mg/kg bw). Al₂O₃‐NPs group received Al₂O₃‐NPs (100 mg/kg bw). SML + Al₂O₃‐NPs group received SML 2 h prior to Al₂O₃‐NPs. The results revealed that Al₂O₃‐NPs significantly increased serum alanine aminotransferase and aspartate aminotransferase activities and serum urea and creatinine levels. Moreover, Al₂O₃‐NPs induced a significant elevation in malondialdehyde level with significant reduction in reduced glutathione content and catalase and superoxide dismutase activities, together with a marked increase of 8‐hydroxy‐2‐desoxyguanosine level in the hepatic and renal tissues. Also, up‐regulations of glutathione‐S‐transferase, tumor necrosis factor‐alpha, and caspase‐3 mRNA gene expressions were recorded in the liver and kidneys. Additionally, Al₂O₃‐NPs induced multifocal areas of necrosis in hepatic parenchyma with glomerular mesangial cell proliferation and glomerular sclerosis in kidney tissues. Conversely, concomitant treatment with sesamol mitigated Al₂O₃‐induced hepatorenal toxicity evidenced by improvement of liver and kidney functions that correlated with regulation of oxidant/antioxidant status, inflammatory, and apoptotic biomarkers and reduction of DNA and tissues damages. In conclusion, sesamol could exert a promising protective role against hepatorenal toxicity of Al₂O₃‐NPs, possibly via its antioxidant, anti‐inflammatory and anti‐apoptotic properties.