BACKGROUND: Urolithiasis is one of the most common urological diseases, and its incidence has increased globally in recent years. Multiple potential mechanisms are involved in urolithiasis, including renal oxidative stress, inflammatory response, fibrosis, pyroptosis, and gut microbiota disturbance. Sodium bicarbonate (NaHCO(3)) is commonly used clinically to alkalize urine and slow the progression of chronic kidney disease, including urolithiasis. However, the specific mechanism of NaHCO(3) in the treatment of urolithiasis is unclear. METHODS: In this study, we constructed a mice urolithiasis model via intraperitoneal injection of glyoxylate (50 mg/kg) for one week in C57BL/6 mice. Meanwhile, 5% NaHCO(3) was added to drinking water in the treatment group. Biochemical detection, immunohistochemical staining, RT-qPCR, and Western blotting were used to assess kidney function and levels of inflammation and pyroptosis. The alteration of gut microbiota in mice treated with NaHCO(3) was measured using 16S rDNA sequencing. RESULTS: The results demonstrated that NaHCO(3) effectively reduced the deposition of CaOx crystal, as well as restored kidney function in urolithiasis-induced kidney injury mice. Moreover, NaHCO(3) alleviated oxidative stress and inflammatory response and ameliorated pyroptosis by modulating the NLRP3 inflammasome pathway in kidney. Additionally, it enhanced the intestinal barrier function by up-regulating the expression of tight junction proteins (ZO-1, occludin, and claudin 5), remodeling the gut microbiota, and reducing intestinal inflammation. CONCLUSION: In summary, NaHCO(3) exerted a protective effect via the gut-kidney axis in the urolithiasis mice model, suggesting its potential use as a dietary supplementation to be added to daily drinking water for the management of urolithiasis.