Our current research aims to evaluate the efficiency of a flavor enhancer, maltol (produced by heating ginseng) against cisplatin-evoked cardiotoxicity by establishing cisplatin-induced heart injury in vivo and H9C2 rat cardiomyocyte model. The cisplatin-treated mice at 3 mg/kg for four times on the 7th, 9th, 11th and 13th day, and in them appeared a serious cardiac damage accompanied with the increase in indicators of heart damage. Multiple exposure of 3 mg/kg for four times of cisplatin increased cardiac cells apoptosis with increased expression of Bax and cleaved-caspase 3, and decreased expression of Bcl-2. Interestingly, supplement of maltol at doses of 50 and 100 mg/kg for 15 days significantly suppressed the cardiac disturbance. In cultured H9C2 cells, maltol enhanced PI3K/Akt expression level during cisplatin treatment, and reduced cisplatin-induced apoptosis. Notably, inhibition of PI3K/Akt by LY294002 and HY-10249A lessened the efficacy of maltol. In mice, maltol apparently induced PI3K/Akt in heart tissues and protected against cisplatin-induced cardiotoxicity. In conclusion, maltol exerted the protective effects against cisplatin-induced cardiotoxicity, at least partially by inhibiting the activation of PI3K/Akt signaling pathways in cardiomyocytes, to ease oxidative stress, and alleviate reactive oxygen species-mediated apoptosis.