Metastatic hormone-sensitive prostate cancer (mHSPC) represents a critical stage in prostate cancer management. Two pivotal phase III clinical trials have demonstrated survival benefit with enzalutamide in mHSPC. This meta-analysis aims to evaluate the efficacy and safety of enzalutamide based on subgroup analyses and reconstructed individual patient-level data.A comprehensive literature search was conducted using PubMed, Embase, Cochrane Library, and ClinicalTrials.gov. The primary outcome was overall survival (OS), while the secondary outcomes included prostate-specific antigen progression-free survival (pPFS), radiographic progression-free survival (rPFS), and adverse events (AEs). The risk ratios (RR) with 95% confidence intervals (CI) was selected as the effect size. Cochran's Q statistic was used to assess the subgroup differences. Survival analysis was performed using Cox hazards model based on the reconstructed individual patient data (IPD). I2 ≤ 50% was regarded as low heterogeneity.The data of 2275 patients were analyzed eventually. Enzalutamide reduced the risk of death by 33% compared to the control. Specifically, enzalutamide reduced the risk of death to 0.64 and 0.84 in subgroups of low and high disease volume, with significant subgroup differences (P = 0.0346). Meanwhile, the risk of death in enzalutamide group was 0.73 among patients without visceral metastases, and 1.06 among those with visceral metastases, indicating significant subgroup differences (P = 0.0124). For geographical regions, Gleason scores, performance status, and docetaxel use, enzalutamide showed consistent effectiveness across all subgroups. Moreover, the risk of grade 3-4 AEs in the enzalutamide group was 1.44 compared to control. No significant heterogeneity was observed.Enzalutamide improves OS, pPFS, and rPFS in patients with mHSPC, and offers greater OS benefit for patients with low disease volume and no visceral metastases. Further investigation should validate these findings in real-world setting, and explore the long-term effect of enzalutamide or more combination regimens of enzalutamide plus other agents.© 2025. The Author(s), under exclusive licence to Springer Nature B.V.