Objectives Multiple physiopathological conditions through stimulate atrogene led to trigger skeletal muscle atrophy, which the regulation of this signaling pathway is still not fully understood. In this study, researchers evaluated the assumptions that saffron extract and resistance training may inhibit muscle atrophy and Atrogene expression, increase testosterone concentration as well as weight in rats with dexamethasone (dex)-induced muscle atrophy. Study design We evaluated the effects of saffron extract and resistance training on atrophic markers in rats with dex-induced muscle atrophy using seven experimental groups. Methods 42 male SD (Sprague-Dawley) rats were randomly distributed into seven subgroups: (1) dex-control (cn), (2) dex-resistance training (tn), (3) dex-saffron feeding 20 mg/kg/day (sa 20 mg), (4) dex-saffron feeding 40 mg/kg/day (sa 40 mg), (5) dex-saffron feeding 20 mg/kg/day + resistance training (sa 20 mg + tn), (6) dex-saffron feeding 40 mg/kg/day + resistance training (sa 40 mg + tn), and (7) healthy control i.e. non-injected dex (cn-i). order to induce muscle atrophy, groups 1 to 6 were intraperitoneally injected with dexamethasone (750 mu g/kg). The resistance training protocol and 20 and 40 mg/kg/day saffron treatments were carried out for 2 months. Results Total weight, soleus, and EDL muscles weight in dex + 20 and 40 mg Saffron, resistance training, resistance training + 20, and 40 mg Saffron groups were significantly increased compared to pre-experimental levels or the health control group (P < 0.05). The serum testosterone level was significantly increased in resistance training + 20 and 40 mg Saffron groups compared to the health control group (P < 0.05). The level of Atrogin-1, Murf-1, and Mir-29b gene expressions in soleus and EDL muscles was significantly elevated in resistance training + 20 and 40 mg Saffron groups compared to the health control group (P < 0.05). Conclusion These findings set saffron alongside resistance exercise as a new target in therapeutic approaches toward clinical conditions causing muscle mass loss.