Monosodium glutamate (MSG) is a flavor enhancer used widely in modern nutrition. The current research aimed at studying the protective effect of Crocin, the main constituent of Crocus sativus L., on MSG-induced cardiotoxicity on male albino rats. The study was performed on 50 adult male albino rats randomly and equally divided into five groups: negative control, vehicle control (received 1 ml saline/day), crocin group (treated with 20 mg/Kg/day crocin dissolved in 1 ml saline), MSG group (received 3 g/Kg/day MSG dissolved in 1 ml saline) and MSG + crocin (treated with MSG and crocin in the same previously mentioned doses). All treatments were gavaged orally once daily for 8 weeks. The results showed that MSG exposure significantly increased total body weight and relative heart weight, serum interleukin (IL)-1β, creatine kinase-myocardial band (CK-MB), Troponin I (CTnI). Also, MSG exposure significantly decreased serum level of IL-10. Cardiac oxidative stress parameters showed elevated malonedialdehyde (MDA) levels, decreased reduced glutathione (GSH) content and depressed cardiac antioxidant enzyme activities. 8- hydroxy-2-deoxyguanosine (8-OHdG) was increased significantly in comparison to the control groups. And there was significant increase in caspase-3 gene expression. These results were supported by histological and immune-histochemical alterations in the heart of MSG-treated rats. Notably, all these changes were partially ameliorated in rats treated concomitantly with MSG and crocin. The results of the present study showed that crocin exerts protective effects against MSG-induced cardiotoxicity in rats.