Highly expressed high mobility group box-1 protein (HMGB1) promotes tumor metastasis. Whether HMGB1 participates in breast cancer cell activation of fibroblasts is unknown. The culture medium of 6 breast cancer cell lines with different migration potential, and with HMGB1 overexpression or knockdown was used to induce fibroblast activation, and collagen and α-SMA expression were measured. We evaluated the migration potential of MDA-MB-231 cells with fibroblasts treated with 3-PO (3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one) inhibitor, anti-HMGB1 treatment, or RAGE (receptor for advanced glycation end products) knockdown. A lung metastasis murine model was used to evaluate whether the RAGE-knockdown fibroblasts mitigates MDA-MB-231 metastasis. Breast cancer cells that are highly migratory and have a high invasive potential, had higher HMGB1 expression and induced greater fibroblast activation strongly than cells with poorer motility. hrHMGB1 and the supernatants of HMGB1-overexpressed MCF-7 cells promoted fibroblast activation, but loss-HMGB1 of MDA-MB-231 abolished potential. Moreover, a novel mechanism was identified by which HMGB1 facilitated fibroblast activation by RAGE/aerobic glycolysis. Consistently, fibroblasts enhanced MDA-MB-231 metastasis, but the enhancement was reversed by 3-PO inhibition, anti-HMGB1 treatment, or RAGE knockdown in vitro and in vivo. We identified that HMGB1 secreted by breast cancer cells promotes fibroblast activation via RAGE/aerobic glycolysis, and activated fibroblasts enhance breast cancer cell metastasis through increased lactate.