This study investigated the eventual protective effects of L-carnitine against renal and liver damage caused by high doses of diclofenac sodium in mice. A pilot study, designed to determine the highest toxic dose of diclofenac, was conducted on 32 Swiss Albino adult mice randomly divided into 4 equal groups according to the drug dose: 0 (control), 2.5 (low), 5 (moderate) and 10 mg/kg/day (high dose) for 5 days by the subcutaneous route. Serum biochemical parameters (BUN and creatinine concentrations and AST, ALT and ALP activities) were measured as well as GSH and MDA contents in liver and in kidney at the end of the treatment. The 2 highest dosages of diclofenac have induced significant increases of the serum markers and MDA accumulation in tissues whereas the kidney and liver GSH contents were depressed in parallel. Besides, a strong dose-effect relationship was evidenced. In the second experimental step, 4 groups of 8 mice received subcutaneous injections for 5 days of saline solution (NaCl, 20 mL/g body weight/day) (group I), of L carnitine (500 mg/kg/day) (group II), of diclofenac sodium (10 mg/kg/day) (group III) and of diclofenac (10 mg/kg/day) plus L carnitine (500 mg/kg/day 3 days before and 2 days during the diclofenac treatment) (group IV) respectively. The diclofenac treatment alone or in combination with L carnitine induced liver and kidney damage as attested by significant increases of the serum markers and by tissue MDA accumulation. Nevertheless, these variations were significantly reduced in co-treated mice. Whereas the GSH pools in liver and kidney were markedly depressed in the group III, they were significantly enhanced in mice treated with L carnitine alone, and remained unaffected in co-treated mice (group IV) compared to the controls. These results demonstrated that the diclofenac toxicity is due to lipid peroxidation and impairment of the antioxidant systems in liver and kidney and that a co-treatment with L carnitine can partially alleviate it by restoring antioxidant capacity.