Asperolide A (AA) treatment inhibited breast cancer development and prevented breast cancer‐induced bone metastasis and osteolysis in vivo. Establishment of breast cancer‐induced bone metastasis nude mouse model and evaluation of AA effects (A). MDA‐MB‐231 cells were injected directly into the tibial plateau. AA inhibited tumor growth in the tibia (B). Body weight of mice (C). Tissue length of tibial tumor section (D). Tissue width of tibial tumor section (E). Tissue volume of tibial tumor section (F). Representative micro‐CT images indicated that AA prevented osteolysis (G). Quantitative analyses of bone structure parameters, including BS/BV (%), BV/TV (%), Tb.N, Tb.Sp (n = 6 per group) (H‐K). Representative tartrate‐resistant acid phosphatase (TRAcP) staining images showed that AA inhibited osteoclast formation (L). Quantitative analyses of TRAcP‐positive cell number (OC.N/BS) and area (OC.S/BS) (M, N). Representative immunohistochemistry images showed that AA inhibited the expression of P‐PI3K (L). Quantitative analyses of P‐PI3K positive area (%) (O). Data are shown as mean ± SD; n = 6 per group; *P < .05, ***P < .001, and ****P < .005, compared with the sham or CTRL groups