Purpose: Treatment for metastatic castration-resistant prostate cancer (mCRPC) includes chemotherapy and inhibition of the androgen receptor pathway. However, the optimal treatment sequence in this scenario is not yet fully understood. Therefore, we conducted a systematic review and meta-analysis comparing cabazitaxel versus abiraterone or enzalutamide for efficacy and safety outcomes as second-line therapy in mCRPC patients after docetaxel failure. Methods: We searched PubMed, Embase, and Cochrane databases for interventional studies comparing cabazitaxel versus abiraterone or enzalutamide for patients with mCRPC who have experienced treatment failure with docetaxel as their first-line therapy. We computed hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs). Results: Eight studies, comprising 1,897 patients were included, of whom 548 (28.8%) received cabazitaxel. Mean follow-up time ranged from 3 to 16.4 months. Median age ranged from 68.1 to 73.9 years in the cabazitaxel group, and 68.0 to 73.1 years in the abiraterone or enzalutamide group. In our meta-analysis, cabazitaxel significantly improved progression-free survival (PFS) rates (HR 0.60; 95% CI 0.47–0.78; p < 0.001) compared to abiraterone or enzalutamide. There were no differences between groups in overall survival (HR 0.76; 95% CI 0.46–1.24; p = 0.27), therapy-related grade ≥ 3 adverse events (AEs) (OR 3.00; 95% CI 0.72–12.40; p = 0.12), and PSA decline ≥ 50% (OR 1.20; 95% CI 0.51–2.80; p = 0.67). Conclusions: In this systematic review and meta-analysis of men with mCRPC after docetaxel failure, second-line therapy with cabazitaxel was associated with a longer PFS compared with abiraterone or enzalutamide, though without a significant difference in OS.