High mobility group box 1 (HMGB1), a critical damage-associated molecular pattern molecule, has been implicated in several inflammatory diseases and cancer types. The overexpression of HMGB1 protein occurs in prostate cancer, and is closely associated with the proliferation and aggressiveness of tumor cells. However, the underlying mechanisms of HMGB1-induced tumor metastasis in prostate cancer remain unclear. In the present study, it was demonstrated that the expression of HMGB1 was high in prostate cancer samples, particularly in the metastatic tissues. Furthermore, recombinant HMGB1 (rHMGB1) enhanced the invasive and metastatic capabilities of the prostate cancer cells. Molecular phenotype alterations of epithelial-to-mesenchymal transition (EMT) and elevated expression levels of matrix metalloproteinase (MMP)-1, -3 and -10 were observed. In addition, advanced glycosylation end-product specific receptor (RAGE) and its downstream molecule nuclear factor (NF)-κB pathway were activated during rHMGB1-induced metastasis. Silencing RAGE or NF-κB reversed the upregulation of MMP and EMT marker expression levels, thus reducing the migration and invasiveness of tumor cells. Taken together, these results suggest that highly expressed HMGB1 drives EMT and the overexpression of MMP-1, -3, -10 via the RAGE/NF-κB signaling pathways, which facilitates the metastasis of prostate cancer and may be a potential therapeutic target for metastatic prostate cancer.