Carbon tetrachloride (CCl₄) is considered an environmental pollutant. Exposure to CCl₄ is commonly associated with nephrotoxicity.  Objective: The aim of this study was to demonstrate the possible preventive role and underlying mechanism of the single and combined administration of captopril and nigella sativa oil against CCl₄ induced nephrotoxicty in male rats. Methods: This study was conducted on sixty four adult healthy male albino rats and divided into 8 groups (8 rats/group). Group I, rats  which served as negative control, group II, rats which given liquid paraffin and saline (positive control), groups III, rats which given captopril in a dose of 100 mg/kg daily by gavage (positive control), group IV, rats which given nigella sativa oil in a dose of 4 ml/kg daily by gavage (positive control), group V, rats which injected i.p. with CCl₄ three times/ week in a dose of 20 μL/100  gm body weight, group VI,  rats which given captopril concurrently with CCl₄ in the same mentioned dose and route, group VII, rats which given nigella sativa oil concurrently with CCl₄ in the same mentioned dose and route; group VIII, rats which given captopril and nigella sativa oil daily concurrently with CCl₄ in the same mentioned dose and route. All rats were given treatment for 6 weeks then sacrificed by decapitation. Biochemical parameters were assessed in all rat groups and statistically analyzed. In addition, histological and immunohistochemical investigations of renal tissues were done. Results: In CCl₄ treated rats, the biochemical assays revealed significant statistical increase in the level of serum urea, creatinine, uric acid and nitric oxide as well as increase level of lipid peroxides, reduced glutathione and superoxide dimutase in the kidney tissue. Histological examination showed degeneration of glomeruli and tubules. High immunolabelling for activated caspase-3 in the kidney was detected on immunohistochemical examination. Treatment with captopril and nigella oil singly or in combination with CCl₄ resulted in improvement of the biochemical, histological and immunohistological changes and this effect is more evident on their combined administration. Conclusion: Captopril and nigella sativa oil can be used as therapeutic agents in protection against CCl₄ induced nephrotoxicity. This effect is attributed to decrease free radicals generation and apoptosis through inhibition of casapse-3 activity in renal tissue. It is recommended to conduct further experimental studies on large numbers and to investigate this effect on nephrotoxic patients.