Prostate cancers at the lethal stage of castration resistance have no means to cure in the clinic. We invented a small peptide approach to trigger a client protein-specific degrading signal for destroying the androgen receptor (AR) protein, the most critical driver in newly developed and post-Abiraterone/ Enzalutamide castration-resistant prostate cancers. The small peptides were derived from the N-terminal segment of the AR protein and were conjugated with a plasma membrane penetrating peptide for prostate cancer-specific uptake. Treatment of AR-positive prostate cancer cells with the small peptides dramatically reduced AR protein levels without affecting the mRNA levels. The AR reduction was not dependent on the ubiquitin-proteasome pathway since the co-treatment of prostate cancer cells with the small peptides with the proteasome inhibitor MG132 did not prevent AR protein reduction. Intra-tumoral injection of the peptides in prostate cancer cell-derived xenografts in nude mice also resulted in suppression of tumor growth. In conclusion, our data suggest that this small peptide approach is feasible to be developed as a novel therapy for advanced prostate cancers.