Background: Nephrolithiasis is a prevalent urological disorder with rising global incidence and recurrence rates. While traditionally considered a luminal disease, increasing evidence suggests that it induces significant histopathological alterations in renal parenchyma, potentially contributing to long-term renal dysfunction. This systematic review and meta-analysis aim to evaluate the spectrum and prevalence of histopathological changes in renal tissue associated with nephrolithiasis. Methods: A comprehensive systematic search of PubMed, Scopus, Web of Science, and Cochrane Library databases was conducted for studies published up to 2025. Studies reporting histopathological findings in renal tissue of patients or experimental models with nephrolithiasis were included. Data were extracted and pooled using a random-effects model. Primary outcomes included crystal deposition, interstitial inflammation, tubular injury, interstitial fibrosis, and glomerular alterations. Results: A total of 28 studies comprising 3,462 subjects were included. Crystal deposition was the most prevalent histopathological finding (72%), followed by interstitial inflammation (65%) and tubular injury (58%). Interstitial fibrosis was observed in 41% of cases, particularly in recurrent nephrolithiasis, while glomerular changes were less frequent (22%). Moderate heterogeneity was noted across studies. Subgroup analysis demonstrated increased severity of histopathological damage in recurrent stone formers and individuals with metabolic comorbidities. Conclusion: Nephrolithiasis is associated with significant structural renal damage, particularly involving tubular and interstitial compartments. These findings highlight the importance of early diagnosis and targeted therapeutic strategies to prevent progression to chronic kidney disease.