BACKGROUND AND AIM: Infertility constitutes a significant global health concern. Cadmium (Cd), a hazardous element, exerts deleterious effects on the reproductive system. Consequently, it is essential to devise novel pharmaceutical strategies to mitigate this adverse effect. Melatonin is linked to the regulation of spermatogenesis across several animals. Ginseng is recognized for its antioxidant capabilities and has shown superior clinical efficacy in male reproductive health. This study aimed to inspect the preventive effects of Melatonin (Mel) and Ginseng (Gin) on the quality of epididymal sperm, as well as testicular function and structure, in rats subjected to cadmium exposure. METHODS: Forty rats were allocated into four equal groups: Control group, Cadmium group: Rats were injected with 2.0 mg/kg, Melatonin group: animals were injected with 10 mg/kg and Ginseng group: Rats were oral gavage with 100 mg/kg. All treatments were maintained for 8 weeks. Testes were taken for histopathological examinations, sperm parameters analysis, biochemical and molecular studies. RESULTS: The results revealed a significant decrease of sperm parameters in Cd group compared to the control group. Nevertheless, treatment with Mel and Gin significantly increased sperm concentration, motility, and viability compared to Cd group (p < 0.05). Besides, Cd treatment caused a significant decrease in SOD and CAT activities and an increase in NO and MDA levels which was significantly improved with Mel and Gin administration (p < 0.05). Apoptosis, inflammation and autophagy markers were significantly inhibited with Mel and Gin treatment. CONCLUSIONS: Melatonin and Ginseng reduce testicular toxicity induced by Cd, via inhibiting oxidative stress, apoptosis, inflammation, and autophagy providing novel insights into combating cadmium toxicity.