Castration-resistant prostate cancer (CRPC) remains a clinical challenge due to resistance to androgen receptor (AR)-targeted therapies such as enzalutamide. Although enzalutamide inhibits AR signaling by targeting the AR ligand-binding domain (AR-LBD), therapeutic resistance frequently develops, highlighting the need for alternative strategies to suppress persistent AR signaling. Targeted protein degradation (TPD) has emerged as a promising modality that can target both the AR-LBD and the AR N-terminal domain (AR-NTD), the latter of which has traditionally been considered an undruggable region. In this study, the anti-cancer activities of several AR-targeting protein degraders (AR-TPDs) with distinct domain-binding properties were comparatively evaluated. AR-NTD-targeting degraders exhibited greater anti-cancer activity than AR-LBD-targeting degraders in enzalutamide-resistant VCaP cells (VCaPEnzR). In addition, combination treatment with enzalutamide and AR-NTD-targeting degraders demonstrated an additive effect based on combination index analysis. Because AR splice variants lacking the ligand-binding domain are implicated in enzalutamide resistance, AR-NTD-targeting degradation may enable elimination of both full-length AR and transcriptionally active variant forms. Collectively, these results highlight the potential of AR-NTD-targeting degraders and support domain-selective protein degradation as a promising strategy for overcoming resistance in CRPC.