Background: Obesity acts as one of most prevalent perilous health affairs. Male obesity -associated secondary hypogonadism (MOSH) is one of many of its complexities, which is mounting in parallel with the aggravation of obesity. Magnetic nanoparticles seem to be advanced favorable trend in multiple biomedical fields. Aim: In this study, we explore therapeutic effects of superparamagnetic iron oxide nanoparticles (SPIONs) coated with carboxymethyl cellulose (CMC) on an obese male rat model with MOSH syndrome, comparing their impacts with a well-known anti-obesity medication (Orlistat). Methods: 42 male albino rats splitted into 7 equal groups: 1-negative control: non-obese, untreated; 35 rats fed the high fat-high fructose (HFHF) diet for period of 12 weeks. Obese rats splitted into 6 equal groups; 2-positive control: obese untreated; 3-obese given Orlistat (30mg/kg); 4-obese given CMC-SPIONs (25mgFe/kg); 5-obese given CMC-SPIONs (50mgFe/kg); 6-obese given CMC-SPIONs(25mgFe/kg) + Orlistat(30mg/kg), 7-obese given CMC-SPIONs (50mgFe/kg) + Orlistat (30mg/kg); all treatments given orally for 4 weeks. During sacrifice, blood serum and sectioned hypothalamic, pituitary, testicular and adipose tissues were collected for biochemical and biomolecular assessments. Results: HFHF-diet for 12 weeks resulted in significant upsurge in BW, BMI, serum fasting glucose, insulin resistance, TAG, TC and LDL-c; HDL-c was dropped. Serum FSH, LH and testosterone values declined. A significant disorder in expression levels of genes regulating HPT-axis pathway. Hypothalamic GnRH, Kisspeptin-1, Kisspeptin-r1 and Adipo-R1 values declined. GnIH and Leptin-R1 values raised up. Pituitary GnRH-R values declined. Testicular tissue STAR, HSD17B3 and CYP19A1 values declined. Adipose tissue adiponectin declined, while leptin raised up. CMC-SPIONs 25mg and 50mg could modulate the deranged biochemical parameters and correct the deranged expression levels of all previous genes. Co-treatments revealed highly synergistic effects on all parameters. Overall, CMC-SPIONs have significant efficiency whether alone or with Orlisat in limiting obesity and consequence subfertility. Conclusions: CMC-SPIONs act as incoming promising contender for obesity and MOSH disorders management, and need more studies to their mechanisms.