The novel compound jesridonin, has extensive anti-tumor activity. In this study, we aim to investigate the cytotoxic effects of jesridonin in combination with paclitaxel. Our results showed that jesridonin in combination with paclitaxel had synergistic cytotoxic effects on human esophageal carcinoma both in vitro and in vivo. Hoechst 33258 staining and the Annexin-V FITC assay demonstrated that paclitaxel synergized with jesridonin in a stronger induction of apoptosis than treatment with paclitaxel or jesridonin alone. Western blotting results revealed that the synergistic apoptosis-induction effects of paclitaxel and jesridonin were mediated by the mitochondrial pathway. This may provide a novel strategy to overcome drug resistance for esophageal cancer therapy.