To investigate the effects of Shuilu Erxian Pills combined with Didang Decoction with modifications on the mitochondrial autophagy signaling pathway in diabetic nephropathy(DN) mice.Methods:Fifty db/db mice were randomly divided into a model group，an irbesartan group(0.026 g/kg)，and low-，medium-，and high-dose Chinese medicine groups(6.27，12.74，and 25.48 g/kg).An additional 10 db/m mice served as the normal control group.All groups received continuous intragastric administration for 8 weeks.Blood glucose(BG)，urinary albumin-to-creatinine ratio(UACR)，reactive oxygen species(ROS)，kidney injury molecule-1(KIM-1)，neutrophil gelatinase-associated lipocalin(NGAL)，and expression levels of LC3，PTEN-induced putative kinase 1(Pink1)，E3 ubiquitin ligase(Parkin)，sirtuin 1(Sirt1)，peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC-1α)，and mitofusin 2(MFN2) were measured.Results:Compared with the normal group，the model group showed significantly increased BG，UACR，KIM-1，and NGAL protein levels(P<0.05)，decreased expression of Pink1，Parkin，LC3，Sirt1，PGC-1α，and MFN2 proteins(P<0.05)，and increased mitochondrial reactive oxygen species level(P<0.05).Compared with the model group，the low-，medium-，and high-dose Chinese medicine groups and the irbesartan group showed decreased BG，UACR，KIM-1，and NGAL protein levels to varying degrees(P<0.05)，increased expression of Pink1，Parkin，LC3，Sirt1，PGC-1α，and MFN2 proteins(P<0.05)，and reduced mitochondrial ROS levels(P<0.05).Conclusion:Shuilu Erxian Pills combined with Didang Decoction with modifications alleviates kidney injury in db/db mice，possibly by upregulating the expression of Sirt1，PGC-1α，and MFN2 in renal tissue and restoring mitochondrial autophagy