Introduction: Although doxorubicin (DOX) is a successful cancer chemotherapeutic, side effects limit the clinical utility of DOX-based therapy, including male infertility and hepatotoxicity. Objective: To evaluate the testicular and hepatoprotective effect of ginseng and/or coenzyme Q10 (CoQ10) in rats exposed to DOX and the possible underlying mechanisms. Materials and Methods:  Fifty adult male albino rats were divided into (10/group), control, DOX group, DOX/Gin group, DOX/CoQ10 group and DOX/Gin+CoQ10 group. Serum testosterone, serum liver enzymes, fasting serum cholesterol and triglyceride (TG), tissue malondialdehyde (MDA), tissue superoxide dismutase (SOD), serum tumor necrosis factor-alpha (TNF-α), serum interleukin 6, serum interleukin 10, nuclear factor E2‐related factor 2 (Nrf2) gene expression in liver and testis and organ indices were measured.  Histopathological and immunohistochemical assessments of apoptotic marker kaspase3 in testis and liver were also performed. Results DOX-induced toxicity is associated with a significant decrease in serum testosterone, testis and liver index values, testicular and hepatic SOD,  testicular and hepatic Nrf2 gene expression and serum interleukin 10. However, there was a significant increase in serum liver enzymes, serum cholesterol and TG, testicular and hepatic MDA, serum TNF-α and serum interleukin 6 when compared with the control group. The combination of ginseng and CoQ10 resulted in significant improvement of DOX-induced changes when compared with other treated groups. Conclusion: Ginseng and CoQ10 have valuable therapeutic effects on DOX-induced testicular and hepatic toxicity via up-regulation of Nrf2 gene expression, inhibition of apoptosis, anti-oxidant, anti-inflammatory and hypolipidemic effects.