BACKGROUND: There is no cross-sectional comparison on therapeutic and adverse effects for treatments of metastatic castration-resistant prostate cancer (mCRPCa). We aimed to horizontally compare them for all common first-line and second-line therapies. METHODS: We conducted a network meta-analysis with a systematic review in four databases (Pubmed, Web of Science, Embase, and Cochrane Library) up to January 5th, 2025. All randomized controlled trials (RCT) related to mCRPCa treatments with a clear description in study design were included. Endpoints included the radiographic progression-free survival (rPFS), overall survival (OS), time to PSA progression (TTPP), PSA progression rate (PSARR), and adverse events. All data was extracted by two researchers and analyzed with Gemtc package in R and Stata15. This NMA protocol was registered online (ID: CRD42025633178). FINDINGS: After screening among 33,694 articles, 24 RCTs involving 13,059 cases were included. For first-line treatments, combination therapies with second-generation androgen receptor inhibitors (ARIs) showed superior efficacies in OS [HR of poly(ADP-ribose) polymerase inhibitors (PARPi) + ARI: 0.63 (0.32,1.25)], TTPP [HR of Lu177 + ARI: 0.07 (0.01,0.87)] and PSARR [RR of Lu177 + ARI: 33.02 (15.56,71.62)] with the highest SUCRA (Surface under the Cumulative Ranking Curve) (72%, 91% and 97% respectively). PARPi + ARI also performed best for rPFS (SUCRA: 85%, with an insignificant HR [0.12 (0.02,2.35)]. For post-docetaxel second-line treatments, ARI also emerged as the preferred option. Efficacies of post-ARI second-line treatments were not evaluated due to the lack of related RCTs. No obvious heterogeneity and publication bias was detected during the therapeutic comparison. INTERPRETATION: This study provided comparative evidence for first-line and post-chemotherapy second-line mCRPCa treatment options. Second-generation ARIs exhibited good efficacy, particularly when combined with other treatments. However, the safety analysis necessitated balance between benefits and adverse events, especially for combination therapies. Stronger evidence is needed through direct comparisons in future clinical trials. FUNDING: The study was supported by The National Natural Science Foundation of China (No. 82172568).