Introduction: Aspartame (Asp) is an artificial sweetener used as a sugar substitute in foods and beverages with no added calories. Quercetin (Qr) is a universal antioxidant ubiquitously present in fruits, flowers, and vegetables. Aim of the Work Study the effect of aspartame on the thyroid gland and the possible protective effect of quercetin on adult male albino rat using histological, and immunohistochemical and morphometric methods. Materials and Methods: Forty adult male albino rats were randomly divided into four equal groups ten rats each: control group, Qr group received 25 mg/kg/day Qr suspension orally for four weeks, Asp group received 250 mg/kg/day Asp orally for four weeks, and Asp-Qr group received Qr and Asp concomitantly in the same dose, duration, and manner as groups II &III. Results: Asp disturbed the normal architecture of the thyroid gland as some follicles fused with each other and others appeared with vacuolated cytoplasm. Different density of colloid was observed. A significant decrease was observed in the mean area % of periodic acid-Schiff stained colloid while a significant increase in the number of Ki-67 positive cells, and histopathological scoring of Asp group were also noticed compared to the control group. Ultrastructurally, dilated RER, swollen mitochondria, and few apical microvilli of follicular cells were observed. The cytoplasm of parafolillicular cells had scanty secretory granules. In contrast, most histological changes disappeared with Qr treatment except for a few irregular or fused follicles. Conclusion: Quercetin significantly improved the histopathological changes induced by Asp on the thyroid gland.