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OBJECTIVE: The purpose of this study was to investigate the synergistic anti-tumor effects of phloretin (Ph) and radiotherapy (RT) on Lewis lung cancer (LLC), and the mechanisms involved. METHODS：The proliferative rate of Lewis cells treated with phloretin was detected by MTT assay; Clone formation experiments were used to demonstrate the synergistic effect of phloretin and radiotherapy; Mice engrafted with the LLC cells were given intraperitoneal injections of saline, phloretin with or without RT. Tumor models were established by laterally transplanting LLC cells in the right thigh of C57BL/J mice. They were randomly divided into four groups, namely saline group, phloretin group, radiotherapy group, phloretin combined with radiotherapy group. 10Gy radiotherapy was performed during the administration. PET-CT was used to detect 18F-FDG uptake in tumor tissue; immunohistochemistry was used to detect Ki67 expression in tumor tissue; cell apoptosis was detected by flow cytometry. RESULTS: Different concentrations of phloretin inhibited the proliferation of Lewis cells in a time and dose-dependent manner (P<0.05). The radiotherapy sensitization ratio (SER) of 50μg Phloretin was 1.645 in the LLC cells. The combination of Phloretin and RT increased survival compared to free Phloretin and RT (p<0.05), and prolonged tumor growth delay (TGD). Furthermore, the RT + Phloretin combination therapy significantly reduced 18F-FDG uptake, increased apoptosis and decreased the proliferation index (Ki67) in tumor cells compared to either monotherapy. CONCLUSION: phloretin combined with radiotherapy has a synergistic anti-tumor effect, possibly by promoting apoptosis, as well as inhibiting proliferation rate and glucose transport.