ETHNOPHARMACOLOGICAL RELEVANCE: Esophageal cancer (EC) is a prevalent malignant tumor with the characteristics of poor prognosis and high mortality in the clinic. Cisplatin (CP), a first-line chemotherapeutic agent, faces the challenge of drug resistance, which hampers its clinical efficacy. In recent decades, traditional Chinese medicine has earned increasing attention for its potential as an adjunct to chemotherapy. Shuang Bailian mixture (SBLM) could significantly enhances the anti-cancer effect of CP in our clinical practices. However, the underlying mechanism of SBLM still needs further investigation. AIM OF THIS STUDY: To investigate the underlying mechanisms that SBLM enhanced the anti-cancer effect of CP. MATERIALS AND METHODS: This study used network pharmacology and molecular docking to obtain the potential active targets of SBLM. Moreover, CCK-8 assay, wound healing, colony formation assays, flow cytometry and Western blotting were used to evaluate the properties of SBLM enhancing the anti-cancer effect of CP. Furthermore, tumor xenograft in nude mice model was used to further determine the potential mechanism that SBLM enhanced the anti-cancer effect of CP. RESULTS: Network pharmacology analysis showed that the PI3K-Akt-Bcl 2 signaling pathway served as the primary target of SBLM. Moreover, SBLM could significantly improve the anti-cancer effect of CP, including inhibited cell proliferation, suppressed colony formation and invasion, and induced cell cycle arrest and apoptosis. Furthermore, SLBM + CP could significantly reduce the tumor sizes on tumor-bearing mice when compared to SBLM and CP treatment. Mechanistically, SLBM could enhance CP effect by inducing cancer cells apoptosis via PI3K-Akt-Bcl 2 signaling pathway. CONCLUSION: Our study revealed the underlying mechanisms that SBLM enhanced the anti-cancer effect of CP through inhibiting the PI3K/Akt/Bcl-2 signaling pathway to induce the cells apoptosis. These results suggest that SBLM could serve as a promising adjuvant in chemotherapeutic regimens for EC.