Emerging evidence has revealed the potential efficacy of Novel Hormonal Agent (NHA) or chemotherapy in high-risk patients with biochemical recurrence (BCR). However, the optimal drug-based treatment strategy remains unknown.We conducted a comprehensive search of the PubMed, Cochrane, and Embase databases up to February 18, 2024 to identify relevant studies. Our analysis focused on outcome measures, including prostate-specific antigen progression-free survival (PSA-PFS), overall survival (OS) and the incidence of adverse events (AEs). A Bayesian network meta-analysis was utilized to indirectly compare the efficacy and safety of various treatment modalities.Four randomized controlled trials with 2074 participants were selected for data extraction and analysis. Treatment combining Androgen Deprivation Therapy (ADT) with Enzalutamide (ENZA) significantly enhanced PSA-PFS as compared to ADT monotherapy (Hazard Ratio (HR) = 0.07, 95% Confidence Interval (CI) 0.01-0.97). The surface under the cumulative ranking curve (SUCRA) indicated ADT + ENZA as the most effective strategy for improving PSA-PFS. In terms of OS improvement, the treatments were ranked as follows: ADT + Docetaxel (DOC), ADT + ENZA, ENZA, and ADT. In terms of adverse event incidence, ADT exhibited the lowest incidence of adverse events, followed by ADT + ENZA. In the meta-analysis, ADT + NHA combined therapy achieved superior efficacy in PSA-PFS and OS than ADT.This study suggests that ADT + NHA, particularly ADT + ENZA, may provide a significant survival benefit and an acceptable safety profile for prostate cancer patients at high-risk BCR. The findings could potentially inform the selection of medications for these patients, although further confirmation through large-scale clinical trials is imperative.© 2025. The Author(s).