Cardiotoxicity is a serious side effect of arsenic trioxide (ATO) which hinders its clinical use in cancer chemo-therapy. Danshensu (DSS) has potential applications in the food and healthcare industry to promote cardio-vascular health. The experiment aims to investigate the effects of DSS against ATO-induced cardiotoxicity and its possible mechanism. Our results demonstrated that DSS improved cardiac dysfunction, alleviated histopatho-logical damage, enhanced antioxidant activity, attenuated cardiomyocyte apoptosis and suppressed inflamma-tion. Further studies showed that DSS prevented ATO-caused activation of NF-kappa B by inhibiting the phosphorylation of AKT and IKK, degradation of I kappa B alpha, and nuclear translocation of NF-kappa B. In H9c2 car-diomyocytes, DSS significantly increased cell survival rate and inhibited ATO-mediated expression of p-AKT, p-IKK alpha/beta, p-I kappa B alpha, and NF-kappa B. Notably, the efficacy of DSS was synergistically increased by AKT inhibitor GSK690693. To sum up, DSS effectively ameliorated ATO-induced cardiac toxicity in vivo and in vitro, which may be achieved through inhibition of the AKT/IKK/NF-kappa B pathway.