INTRODUCTION: Percutaneous nephrolithotomy is the gold standard for large renal stones, with prone and supine positions offering distinct advantages and disadvantages. This meta-analysis compares the efficacy and safety of these two approaches. METHODS: This meta-analysis registered in PROSPERO (CRD42024603670) followed PRISMA and AMSTAR guidelines, including RCTs, cohort, and case-control studies comparing SP and PP PCNL for renal stones. It assessed demographic data, stone-free rate, operative time, hospital stay, complications and hemoglobin drop, with bias risk evaluated using Cochrane and ROBINS-I tools and statistical analysis performed in Jamovi. RESULTS: 43 studies with 11774 patients were included. No significant differences were found in patient characteristics, SFR (RR = 0.9945, p = 0.7008), hemoglobin drop (p = 0.0800), or hospital stay duration (p = 0.1942). The SP group showed shorter OT (SMD = -0.3895, p = 0.0084), fewer overall (RR = 0.8692, p = 0.0026) and major complications (RR = 0.7461, p = 0.0151). SP also had lower rates of visceral injury (RR = 0.8485, p = 0.1581), transfusion (RR = 0.8514, p = 0.1497), sepsis (RR = 0.7880, p = 0.1304), urinary leakage (RR = 0.7699, p = 0.2681), and pleural effusion (RR = 0.5564, p = 0.0898), but these were not statistically significant. CONCLUSION: This meta-analysis found no significant differences between SP and PP in demographics, stone size, SFR, hospital stay, or hemoglobin drop. However, SP was associated with shorter OT, fewer complications and major complications, suggesting it is a viable alternative.