Background: Chitosan is a promising natural source for controlling obesity. Obese people tend to use supplementary nutrients to compensate for their deficiencies in their diets. The present study aimed to investigate the combined effect of chitosan, calcium, and vitamins A and E supplements against the adverse effects of high-fat diet consumption in rats. Methods: Twenty-five male albino rats were assigned into five equal groups. Control rats were fed standard basal diet (SBD). Another group was fed high-fat diet (HFD) without supplements. The other three groups were fed HFD containing 0, 400, and 800 mg of chitosan per kilogram diet, in presence of calcium and vitamins A and E supplements, daily for 10 weeks. Results: As compared to controls, rats fed HFD without supplements showed significant elevations in body weight gain, feed consumption, relative weights of the heart and liver, serum levels of total cholesterol, triglycerides, low-density lipoprotein cholesterols, very low-lipoprotein triglycerides, urea, creatinine, and malondialdehyde, as well as serum activities of alanine and aspartate aminotransferases, alkaline phosphatase, and creatine kinase. Moreover, significant declines in the relative kidney weight, serum levels of high-density lipoprotein cholesterols, total proteins, albumin, globulin, calcium, vitamins A and E, erythrocyte glutathione content, and superoxide dismutase activity were recorded. Histopathological alterations were observed in rats fed HFD with or without supplements. On contrary, rats fed HFD containing chitosan and supplements showed remarkable improvement in all the studied parameters towards control values, in dose-dependent manner. Conclusion: Chitosan, calcium, and vitamins A and E attenuated the adverse effects caused by HFD intake in rats.