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This study aims to investigate the effect of Premna odorata (P. odorata) (Lamiaceae) on the hepatic and nephrotoxicity induced by aluminum chloride (AlCl3) in rat. Wistar male rats were equally classified into four groups: control, P. odorata extract (500 mg/kg B.W.), AlCl3 (70 mg/kg B.W.), and P. odorata extract plus AlCl3 groups. All treatments were given orally for 4 weeks. Serum transaminases and some biochemical parameters, hepatic and renal antioxidant/oxidant biomarker; tumor necrosis factor-α (TNF-α); matrix metalloproteinase (MMP9) and transforming growth factor-β (TGF-β) mRNA expression; histopathological examination of the liver, and kidneys were investigated. The obtained results revealed that AlCl3 significantly increased the activities of serum aspartate transaminase, alanine transaminase, and alkaline phosphatase as well as produced a significant increase in total cholesterol, triglyceride, urea, and creatinine concentrations, while there were no changes observed in the total protein, albumin, and globulin concentrations. Also, aluminum administration significantly decreased the reduced glutathione content and increased the catalase activity, malondialdehyde, and TNF-α concentrations in the liver and kidney tissue. Moreover, AlCl3 results in congestion, degeneration, and inflammation of the liver and kidney tissue. Co-treatment of P. odorata extract with AlCl3 alleviated its harmful effects on the previous parameters and reduced the histopathological alterations induced by AlCl3. Therefore, Premna odorata may have a potent protective effect against oxidative stress induced by Al toxicity through downregulation of MMP9 and TGF-β gene expression.