Myocardial toxicity is one of the major side effects of many chemotherapeutics. It has been shown that propofol can ameliorate the cardiotoxicity of chemotherapeutic agents. In this study, we intend to investigate the role of the PI3K-Akt-Bad signaling pathway in propofol relief of doxorubicin-induced oxidative stress and apoptosis in rat cardiomyocytes. Cultured neonatal rat cardiomyocytes were treated with vehicle, doxorubicin, propofol, or propofol plus doxorubicin in the presence or absence of the PI3K inhibitor LY294002. Cells were harvested 20 h post-exposure to doxorubicin followed by analysis of their cellular taurine content, oxidative/nitrative stresses, and cellular apoptosis. The activation of the PI3K-Akt pathway was analyzed by immunoblotting. FACS, TUNEL, and LDH assays showed that the viability of cardiomyocytes was markedly reduced by doxorubicin, but was improved by propofol. Doxorubicin treatment significantly elevated cellular reactive oxygen and nitrogen contents while lowering the levels of taurine, Akt, and phosphorylated Akt and Bad. The abovementioned doxorubicin-induced changes were reversed by propofol. The protective effects of propofol were abrogated by simultaneous treatment with LY294002. In conclusion, the PI3K-Akt-Bad pathway plays a critical role in conferring the protective effects of propofol against myocardial toxicity from doxorubicin.