<p>Percutaneous nephrolithotomy (PCNL) is the gold-standard treatment for large renal and upper ureteral stones. Continuous irrigation is essential for visualization, thermal control, and fragment clearance but carries risks such as hypothermia, electrolyte imbalance, elevated intrarenal pressure, and infection. This review summarizes current evidence on irrigation strategies during PCNL and provides recommendations to mitigate these risks. A systematic literature search was conducted for English-language full-text articles published up to January 2025, using terms related to PCNL and irrigation. Eligible designs included randomized controlled trials, cohort studies, case–control studies, and case series. Reviews, editorials, and duplicates were excluded. A total of 553 abstracts were screened by a single reviewer, with 28 studies meeting inclusion criteria. Reference lists were hand-searched for additional sources. Evidence highlights multiple determinants of irrigation safety and efficacy. Distilled water and other hypotonic solutions were associated with electrolyte shifts, whereas saline maintained stability. Additives such as tranexamic acid reduced intraoperative blood loss, transfusion rates, and hospital stay without added complications, while povidone-iodine or antibiotic irrigation showed promise in reducing postoperative fever and sepsis. Warmed irrigation fluid mitigated hypothermia but raised concerns of bleeding and thermal injury. Excessive irrigation volume and prolonged operative duration consistently correlated with greater systemic absorption, hemodynamic instability, and electrolyte changes. Irrigation parameters directly influence perioperative safety and outcomes in PCNL. Although isotonic saline remains the standard, antifibrinolytic and antimicrobial additives, individualized temperature management, and optimized volume control represent promising strategies.</p>