<p>Human epidermal growth factor receptor 2 (HER2/ERBB2) is a well-established therapeutic target in breast and gastric cancers, but its relevance in prostate cancer (PC) remains unresolved. Although HER2 gene amplification is relatively uncommon in PC, heterogeneous overexpression has been observed, particularly in advanced and castration-resistant PC (CRPC), where it is frequently associated with aggressive clinicopathological features. Experimental studies portray HER2 as a signaling hub, mediating crosstalk with androgen receptor (AR) signaling to sustain tumor growth under androgen-deprived conditions. Concurrent activation of the HER2-PI3K-AKT axis further promotes cell survival, proliferation, and therapeutic adaptation. Moreover, HER2 cooperates with epidermal growth factor receptor (EGFR) and NF-κB pathways, reinforcing tumor plasticity and resistance mechanisms. Despite these compelling biological insights, clinical translation has been disappointing. Early trials with Trastuzumab, Lapatinib, and Pertuzumab yielded minimal benefit, underscoring patient heterogeneity, pathway redundancy, and the lack of biomarker-guided stratification. Lessons from these failures highlight the need for precision oncology approaches that integrate molecular profiling and rational therapeutic combinations. Recent advances, including next-generation HER2-targeted antibody-drug conjugates, bispecific antibodies, and CAR-T cell therapies, as well as strategies combining HER2 inhibition with AR signaling blockade, PI3K/AKT inhibitors, or immunotherapy, offer renewed promise. HER2 in PC thus represents a paradox: biologically significant but clinically underexploited. Reframing HER2 within the AR-PI3K signaling network and leveraging biomarker-driven strategies may finally unlock its therapeutic potential. This review critically examines HER2 in PC, analyzing its mechanistic roles, therapeutic potential, and the challenges that shape its value as both a prognostic biomarker and actionable target.</p>