Purpose. Our aim is to evaluate the safety and efficacy of endoscopic combined intrarenal surgery compared to percutaneous nephrolithotomy to guide practitioners and inform guidelines. Materials and Methods. A detailed database search was performed in PubMed, OVID, Scopus, and Web of Science in October 2021 to identify articles pertaining to ECIRS published between 2001 and 2021. Results. Four nonrandomized comparative studies and one RCT were identified, yielding five studies with a total of 546 patients (ECIRS/mini-ECIRS, n = 277; PCNL/mini-PCNL, n = 269). Subjects in these five studies met the predefined inclusion criteria established by two reviewers (J.E.A. and R.L.S.) and were therefore eligible for analysis. The results demonstrated that ECIRS was associated with a higher SFR (OR: 4.20; 95% CI: 2.79, 6.33; p < 0.00001 ), fewer complications (OR: 0.63; 95% CI: 0.41, 0.97; p = 0.04 ), and a shorter hospital stay (WMD: −1.27; 95% CI: −1.55, −0.98; p < 0.00001 ) when compared to PCNL. There were no statistically significant differences in blood transfusions (OR: 0.45; 95% CI: 0.12, 1.68; p = 0.24 ), operative time (SMD: −1.05; 95% CI: −2.42, 0.31; p = 0.13 ), or blood loss (SMD: −1.10; 95% CI: −2.46, 0.26; p = 0.11 ) between ECIRS and PCNL. Conclusions. ECIRS may be a more suitable approach for the surgical management of large and complex kidney stones currently indicating PCNL due to its superior efficacy with comparable surgical time and complication rate, though it is thought that a lack of resources and properly trained personnel may preclude ECIRS from becoming the standard. It is our impression that ECIRS may become the preferred technique in the endourologic community corresponding to the evolutionary sequence of percutaneous stone surgery.