Background:  Cadmium (Cd) is an industrial and environmental pollutant that exerts adverse effects on different organs in humans and animals. Endocrine organs, such as the thyroid, kidneys, testis, and placenta, are sensitive to the toxic effects of Cd. Ziziphus spina-christi fruit has been claimed to exhibit potent anti-oxidative and free radical scavenging abilities. Aim: This work is mainly designed to evaluate the potential modulatory role of Z. spina-christi fruit extract against thyroid, kidney, and testicular impairments associated with cadmium chloride (Cd Cl2) exposure in rats. Material & Methods: Twenty-four male rats were divided into four groups (n = 6): group I served as control, group II was supplemented daily with Ziziphus fruit extract (200 mg/kg b.wt), group III was treated with CdCl2 (5 mg/kg b.wt) each other day, and group IV was administered with CdCl2 simultaneously with Ziziphus fruit extract. The experiment was conducted for 45 days. At the end of the experiment, the rats of all groups were weighed and sacrificed, and the thyroid, kidneys, and testes were immediately excised, and processed for histological and biochemical evaluation of antioxidants and apoptosis. Also, blood samples were collected and analyzed to estimate the appropriate biochemical parameters for each organ. Results: In CdCl2 treated rats, the levels of serum hormones (TSH, T3, T4, FSH, LH, and testosterone) were significantly decreased if compared with control. Additionally, the levels of calcium, phosphorus ions, and albumin were also decreased while the level of total cholesterol was significantly elevated compared with the control. Moreover, the levels SOD and GSH were significantly lowered while the level of MDA was elevated in the tissues of all target organs   (thyroid, kidney, and testes). Also, the sections from the thyroid, kidney, and testes displayed pronounced deleterious histological changes. Furthermore, the mean % values of positively expressed cells for caspase-3 and annexin-v markers were significantly elevated in the thyroid and testicular tissues of CdCl2 received rats compared to control. Co-supplementation of Z. spina-christi fruit extract to CdCl2 exposed rats successfully restored the altered biochemical and histological and apoptotic changes induced by cadmium. Conclusion: It is concluded that Z. spina-christi fruit extract has a powerful protective role against Cd-induced deleterious biochemical and histological changes in the thyroid, kidneys, and testes of male rats.