Bone metastasis is the major cause of mortality associated with prostate cancer. Whereas activin A is known to inhibit prostate cancer cell growth and promote apoptosis, the correlation of elevated activin A with increasing serum prostate-specific antigen (PSA) levels in bone metastatic stages of prostate cancer is well documented. The molecular mechanisms explaining these paradoxical effects of activin A and how activin A influences the progression of prostate cancer with bone metastasis remain unclear. By comparing expression profiles of primary prostate cancer biopsies, with and without bone metastasis, we discovered that the expression of activin A is increased in cases with bone metastatic propensity and correlates with increased androgen receptor (AR), PSA expression, and Gleason scores. Activin A promotes migration of prostate cancer cells to osteoblasts, elevates the AR gene transcription through Smads through binding to AR promoter, and induces nuclear translocation of AR to interact with Smad3. Knockdown of Smad3 by siRNA decreases activin A-promoted AR expression and cancer cell migration. Overexpression of AR reversed Smad3-siRNA suppression on activin A-mediated cell migration to osteoblasts. These data suggest that activation of the AR through Smads is required for activin A-promoted prostate cancer cell migration to bone matrix, thereby promoting the bone metastatic phenotype, and the activin A-Smad-AR axis may be considered a therapeutic target in bone metastatic diseases.