Casticin, a polymethoxyflavone derived from natural plants, has biological activities including induction of cell apoptosis. In this study, we showed the beneficial effects of casticin on the inhibition of prostate cancer cell metastasis. Casticin reduced total viable cell number, thus, we selected low doses of casticin for following experiments. Casticin decreased cell mobility, suppressed cell migration and invasion, and reduced cell gelatinolytic activities of MMP‐2/‐9. Furthermore, casticin inhibited the protein levels of AKT, GSK3 αβ, Snail, and MMPs (MMP‐2, ‐9, ‐13, and ‐7) at 24 and 48 hr treatment. Casticin diminished the expressions of NF‐κB p65, GRB2, SOS‐1, MEK, p‐ERK1/2, and p‐JNK1/2 at 48 hr treatment only. However, casticin reduced the level of E‐cadherin at 24 hr treatment but elevated at 48 hr. The novel findings suggest that casticin may represent a new and promising therapeutic agent for the metastatic prostate cancer. Practical applications Casticin derived from natural plants had been used for Chinese medicine in Chinese population for thousands of years. In the present study, casticin attenuated metastatic effects, including decreasing viable cell number, inhibiting the migration, invasion, and adhesion, and reducing matrix metalloproteinases activity on human prostate DU 145 cancer cells. In addition, the results also provided possible pathways involved in casticin anti‐metastasis mechanism. We conclude that casticin may be an aptitude anticancer agent or adjuvant for the metastatic prostate cancer in the future.