Male infertility can occur due to environmental factors such as exposure to heavy metals. Cadmium is one of the heavy metals that leads to infertility on prolonged exposure. Quercetin is a naturally occurring dietary flavonoid with antioxidant, anti-inflammatory, hepatoprotective and neuroprotective effects. We aim in this study to evaluate the role of silent information regulator 1 (SIRT1) in the protective effect of quercetin on cadmium-induced testicular damage in rats. In the current study, testicular injury was induced by cadmium. The study was carried out on forty adult male albino rats divided into four groups. Group (I): Normal control group. Group (II): Quercetin group. Group (III): Cadmium group. Group (IV): Cadmium + Quercetin group. At the end of the experiment, we measured reproductive hormones, epididymal sperm functional parameters, testicular reduced glutathione, superoxide dismutase activity and malondialdehyde. Immunoassays of Bcl-2 & tumor necrosis factor alpha (TNF-α), testicular apoptotic marker caspase -3 were done. We assessed the testicular expression of SIRT1 by real-time PCR. Testicular expression of COX-2 was assayed by immunohistochemical staining. A histopathological examination of testicular tissue was done. Our results revealed that cadmium-induced testicular histological injury enhanced oxidative stress and apoptosis, paralleled with down-regulation of SIRT1. Quercetin co-treatment displayed antioxidant/anti-apoptotic efficacy increased SIRT1 level, improved reproductive hormones axis and fertility parameters. We concluded that SIRT1 integrates testicular quercetin-mediated intracellular transduction cascades in cadmium-induced testicular damage.