The toxic effect of diclofenac (DCF) sodium and Ciprofloxacin (CIP) on gene expression of cytochrome P450 oxidase (CYPs) and the histology of liver and kidney of male albino rat has been evaluated in this study. DCF and CIP were chosen since they are inhibitors for specific CYP enzymes. Thirty-five adult male albino rats were divided into 7 groups of 5 animals each (A, B, C, D, E, F and G) and were treated orally with drugs for 21 consecutive days. Group A served as the control while B and C were treated with 5.3, 10.6 mg/kg body weight (bw) DCF sodium and groups D and E were treated with 40 and 80 mg/kg bw CIP, respectively. Groups F and G were treated with a mixture of the low and the high doses of both drugs, respectively. Both drugs significantly downregulated the mRNA expression of CYP1a2, CYP3a4 and CYP2c9. They caused hepatorenal histological changes. In the liver, massive fibrosis, necrosis, inflammatory cell infiltration with hemorrhages and hydrophilic degeneration have been observed. A massive tissue injury with glomerular and tubular damages due to sever necrosis, degeneration of concomitant inflammatory cells and blood vessels congestion have been shown in renal tissues. Although DCF and CIP are still used as therapeutic drugs, their use should be limited as their chronic administration induces a toxic effect on human health.