Objective: To investigate the clinical efficacy of flexible negative pressure suction sheath combined with flexible ureteroscopic lithotripsy (FURL) for renal calculi and the impact on serum cystatin C (Cys-c) and C-reactive protein (CRP) levels in the patients. Methods: The clinical data of 120 patients with renal calculi who underwent FURL in the hospital from January 2023 to December 2025 were retrospectively analyzed. According to the type of ureteral access sheath used during operation, the patients were assigned to the observation group (flexible negative pressure suction sheath, n=60) and the control group (traditional flexible ureteroscopic sheath, n=60). The two groups were compared in terms of operation-related indicators (operation time, intraoperative blood loss, postoperative hospital stay), stone clearance rate, Cys-c and CRP levels on postoperative day 7, and postoperative complication rate. Results: Compared to the control group, the observation group demonstrated decreases in operation time, intraoperative blood loss, postoperative hospital stay, Cys-c and CRP levels on postoperative day 7, and postoperative complication rate, and an increase in the stone clearance rate (P<0.05). Conclusion: The combined treatment with flexible negative pressure suction sheath and FURL is effective for renal calculi. It can effectively shorten the operation time and postoperative hospital stay, reduce intraoperative blood loss, improve the stone clearance rate, lower postoperative inflammatory response and the risk of renal function injury, with a lower incidence of complications.