Renal stones are prevalent urinary tract disorders, with management strategies influenced by factors such as stone size, location, complexity, and patient characteristics. Percutaneous nephrolithotomy (PCNL) is a reliable treatment option for large, complex renal stones and staghorn calculi, offering efficient stone clearance with a low incidence of significant complications. In cases involving multiple calyces, accessing all areas through a single tract can be challenging, making multiple-tract PCNL a preferred method for enhanced stone clearance and reduced reliance on secondary treatments like extracorporeal shock wave lithotripsy (ESWL). However, this approach has raised concerns regarding increased bleeding and transfusion rates. A retrospective analysis of 500 consecutive PCNL procedures conducted at a tertiary referral center from January 2014 to December 2022 evaluated the effectiveness and safety of multi-tract versus single-tract PCNL. Results indicated that multi-tract procedures were performed in 50 cases (10%), characterized by larger stone burdens and more complex S.T.O.N.E. scores compared to the 450 cases (90%) undergoing single-tract PCNL. Although single-tract PCNL showed shorter operation times and hospital stays, the stone-free rates (86% vs. 84%) and complication rates (36% vs. 22%) between the two approaches were not significantly different. This study concluded that multi-tract PCNL is an effective and safe alternative for patients with large and complex stone burdens, suggesting the need for future research to assess its potential in minimizing subsequent interventions for achieving stone-free status.