Urolithiasis, a prevalent condition affecting at least 3% of the population, presents significant challenges globally. In the Republic of Uzbekistan, the incidence of urolithiasis has risen by 25.8% from 2017 to 2020. While external lithotripsy remains a preferred treatment, it can induce traumatic effects on kidney parenchyma, leading to inflammatory changes. The search for less invasive treatments with fewer complications is ongoing. Methods: This study examined 90 urolithiasis patients treated between 2017 and 2020 at the Bukhara Regional Multidisciplinary Medical Center. Patients underwent extracorporeal shock wave lithotripsy (ESWL), and specific kidney damage markers (lipocalin-2, cystatin-C) were evaluated alongside conventional assessments. Patients were divided into two groups based on the number of ESWL sessions. A control group of 32 individuals without urolithiasis was also included. Results: Initial serum creatinine, glomerular filtration rate (GFR), lipocalin-2, and cystatin-C levels were within normal ranges for all urolithiasis patients before ESWL. Significant increases in lipocalin-2 and cystatin-C levels in serum and urine were observed post-ESWL, particularly after multiple sessions. While markers decreased in the first group over time, they remained elevated in the second group, indicating persistent renal parenchymal damage. Conclusion: Assessment of lipocalin-2 and cystatin-C levels in serum and urine proves promising for non-invasive monitoring of renal parenchyma status, aiding treatment effectiveness evaluation and timely intervention. Repeated ESWL sessions exacerbate renal parenchymal damage, emphasizing the need for optimized patient management and nephroprotective therapies. These findings highlight the importance of refining treatment approaches to minimize adverse outcomes in urolithiasis patients undergoing ESWL