Background: The treatment landscape of metastatic castration-resistant prostate cancer (mCRPC) has evolved tremendously, while little is known about the efficacy and safety comparison between current first-line mCRPC systemic therapies in the overall patient population and in the context of clinically relevant subgroups. Methods: We conducted a systematic literature review and network meta-analysis (NMA) of randomized controlled trials (RCTs). Multiple databases (PubMed, Embase, and Cochrane Library), ClinicalTrials.gov, and major congress abstracts were searched in the first-line treatment of mCRPC. The primary efficacy outcomes were radiographic progression-free survival (rPFS) and overall survival (OS). The safety outcomes were adverse events (AEs), serious AEs (sAEs), and grade ≥3 AEs. Two separate pairwise meta-analyses were conducted since there were no common arms between therapies with and without docetaxel (Doc) when considering OS and safety outcomes, while only trials without Doc assessed rPFS. Moreover, we performed subgroup analyses according to treatment regimens and homologous recombination repair (HRR) gene alteration status. Results: The analysis included data from 35 clinical trials (38 references) published as of June 6, 2023, comprising a total of 24,400 patients. For the non-Doc group, analysis of treatment ranking revealed that PARPi doublet, especially talazoparib plus enzalutamide, had the highest likelihood of improving rPFS and OS compared with ARSI doublet, ARSI monotherapy, and immunotherapy, mainly in the HRR-deficient patients while raising some concerns about safety profiles. Regarding therapies based on Doc, most Doc doublet regimens demonstrated subtle improvement in OS compared to Doc monotherapy with tolerable toxicity. Conclusions: This systematic review and meta-analysis provided a comprehensive analysis of the therapeutic effects and safety profiles of various first-line mCRPC systemic therapies. Our findings may provide decision-making guidance to clinicians and help inform mCRPC patients-centered treatment regimens. In an era of PARPi combination with ARSI, unfortunately, because of the lack of common arm delivery of Doc, we cannot estimate the relative value of Doc versus non-Doc as first-line mCRPC therapies.