Background: Although previous studies have compared the minimally invasive simple prostatectomy (MISP) with open simple prostatectomy (OSP) for large prostates, there is still controversy. This study aims to provide the latest evidence for clinical practice. Materials and Methods: We systematically searched Science, EMBASE, PubMed, and Clinicalkey databases for articles comparing MISP and OSP for large prostates. Result parameters including International Prostate Symptom Score (IPSS), quality of life (QoL), maximum urine flow rate (Q(max)), postvoid residual urine volume (PVR), operative time (OT), estimated blood loss (EBL), irrigation time (IT), catheterization time (CT), length of hospital stay (LOS), transfusion rate (TR), and complications were evaluated using RevMan 5.3. Results: A total of 995 patients were included in 10 studies. No statistically significant differences were found between two groups in IPSS (weighted average difference [WMD] = -0.36, p = 0.26), QoL (WMD = -0.22, p = 0.05), Q(max) (WMD = 0.46, p = 0.62), and PVR (WMD = -2.14, p = 0.65). The MISP group had similar IT (WMD = -1.52, p = 0.06), lesser EBL (WMD = -292.22, p < 0.001), shorter CT (WMD = -1.89, p < 0.0001), shorter LOS (WMD = -2.52, p < 0.001), lower TR (odds ratio [OR] = 0.21, p < 0.001), and lower complications (OR = 0.49, p < 0.001) compared with OSP group. However, the OT (WMD = 43.07, p < 0.001) of MISP was longer than that of OSP. Conclusions: The present results demonstrated that MISP provided similar efficacy to those of OSP while maintaining a better security. Our findings imply that MISP is a feasible and effective alternative to the OSP.