〔Abstract〕 Objective To investigate the effect of legumain knockout and icaritin on bone metastasis in breast cancer. Methods Wild-type and legumain knock-out mice were operated for heart injection, and the therapy group was treated with icaritin. Micro-CT was used to detect bone erosion caused by bone metastasis in breast cancer. Western blot experiments were used to detect relevant indicators. Results Mice with legumain knock out alone could slightly alleviate bone metastasis in breast cancer. Combined with icaritin,they could effectively alleviate bone metastasis in breast cancer via affecting signal transducer and activator of transcription-3(STAT3), glycogen synthase kinase-3β(GSK3β), β-catenin pathways. Conclusion Legumain knockout cooperated with icaritin can effectively relieve breast cancer bone metastasis.