Background: Renal interstitial fibrosis (RIF) represents the final common pathway in nearly all progressive chronic kidney diseases. This study aimed to investigate the effects of Yishen-Huoxue formula (YHF) on RIF and its underlying mechanisms.Methods: Unilateral ureteral obstruction (UUO) model was applied to induce RIF in vivo. Thirty-six male SD rats were randomized into six groups: sham group, UUO group, UUO + Losartan group, and UUO + YHF-L/M/H groups. The histopathological changes of rat kidney and its function were evaluated 14 days post-UUO. miRNA sequencing and differential gene analysis identified miR-210 as a potential target of YHF treatment. Western blot and qRT-PCR were employed to assess the impact of miR-210 overexpression and knockdown on the expression of hypoxia-related factors in HK-2, NRK-52E, HUVEC, and 293T cells under hypoxic conditions. Cell proliferation, migration, and angiogenesis were determined using CCK-8 assays, transwell assays, and tubule formation assays, respectively.Results: In vivo, YHF treatment significantly attenuated RIF, protected renal function, increased miR-210 expression, and decreased the expression of HIF-1α, BNIP3, and NIX in the serum exosomes of UUO rats. In vitro experiments revealed that miR-210 downregulates the expression of HIF-1α and its downstream factors, mitigating hypoxia-induced cellular injuries, including decreased cell viability, migration ability, and angiogenesis capability. Further experiments demonstrated that YHF treatment upregulated miR-210 expression while downregulating HIF-1α expression in HK-2 cells under hypoxic conditions. Meanwhile, YHF alleviated hypoxia-induced renal cell damage and impaired angiogenesis in HUVECs, with miR-210 mimic enhancing and miR-210 inhibitor attenuating these protective effects.Conclusion: Yishen-Huoxue formula alleviates RIF by mediating the miR-210/HIF-1α pathway to attenuate hypoxia-induced renal cell injury and promote angiogenesis.