Objective: To investigate the cardioprotective effect of beta-glucan against isoproterenol-induced cardiotoxicity in rats, and elucidate the underlying mechanism. Methods: Rats were orally pretreated with beta-glucan (40 mg/kg body weight) for 30 d, and isoproterenol (20 mg/100 g body weight) was administered on days 31 and 32. The effects of beta-glucan on markers of cardiac injury, hemodynamic changes, production of proinflammatory cytokines, and the corresponding mRNA expressions were evaluated. In addition, histological analysis was performed. Results: Pretreatment with beta-glucan prevented isoproterenolinduced cardiac injury by preserving the structural and functional integrity of the plasma membrane and attenuating the production of proinflammatory cytokines (NF-κB, TNF-α, IL-6, IL-1β, and IFN-γ) in the heart. Moreover, beta-glucan significantly downregulated the mRNA expression of ACE, AT1R, TNF-α , IL-6, NF-κ B, caspase-3, TLR-4, and Bax, and upregulated Bcl-2 in the heart. At the same time, pretreatment with beta-glucan alleviated myocardial damage as reflected in a reduction in myonecrosis, edema, and erythrocyte extravasation with almost imperceptible inflammation. Conclusions: Beta-glucan can protect against isoproterenol-induced cardiotoxicity by attenuating cardiac inflammation and apoptosis and regulating the ACE-AT1R axis, thereby preventing cardiac remodeling. © 2023 Elsevier B.V., All rights reserved.