Objective: To investigate the effect and possible mechanism of total flavonoids of Desmodium styracifolium (TFDS) on the formation of renal calcium oxalate stones. Method: Selective macrophage Rictor gene knockout mice (Csf1r Cre -/-, Rictorfl/fl, C57BL/6J) and their control group mice (Csf1r Cre+/-, Rictorfl/fl, C57BL/6J) were used to establish renal calcium oxalate stone models, and TFDS intervention was administered. Collect kidney tissues from various groups of mice for routine staining, immunohistochemical fluorescence staining, flow cytometry, and other examinations to explore the effect of TFDS on the formation of renal calcium oxalate stones; Primary extraction of bone marrow-derived macrophages (BMDMs) from the two types of mice was performed, and TFDS intervention was administered to investigate the mechanism through PCR, cell fluorescence staining, flow cytometry, and other examinations. Result: The number of renal calcium oxalate stones in the renal tissue of mice with renal calcium oxalate stones+knockout group was significantly higher than that in the renal calcium oxalate stone group, accompanied by a significant increase in polarization of M1 macrophages; After TFDS intervention in two groups of mice, the renal tissue of the TFDS+renal calcium oxalate stone group showed a significant decrease in renal calcium oxalate stones and M1 macrophage polarization, while the formation of renal calcium oxalate stones in the TFDS+renal calcium oxalate stone+knockout group showed no significant changes compared to the non-intervention group. Cell experiments showed that after Rictor knockout, BMDM exhibited significant polarization of M1 macrophages, while polarization of M1 macrophages was significantly reduced in the TFDS+BMDM group; however, there was no significant change in polarization after TFDS intervention in Rictor knockout of BMDM compared to before intervention. Conclusion: TFDS can effectively and safely reduce the formation of renal calcium oxalate stones in vitro, possibly by inhibiting Rictor regulated polarization of M1 macrophages.