High-fat diet (HFD) feeding is a risk factor for kidney damage with limited treatment options. This study explored the effect of total glucosides of paeony (TGP) for treating obesity-related kidney damage. C57BL/6 mice fed with HFD were used for in vivo experiments. Body weight, lipid and renal function indicators were measured. Hematoxylin and eosin, Masson, Sirius Red and F4/80 immunohistochemical staining were performed. Fibrosis levels, inflammatory factors, MyD88, IκB and p-Jun NH2-terminal kinase (JNK) were detected. SV40 cells were incubated with palmitic acid, transfected with siRNA MyD88 and/or treated with TGP. The expression of MyD88, IκB, p-JNK, fibrosis and inflammatory factors were detected. TGP considerably decreased HFD-induced body weight gain and serum lipid concentration but improved renal function. In addition, TGP inhibited renal fibrosis and inflammation and reduced MyD88 and p-JNK levels, whereas increased IκB levels. Moreover, silencing MyD88 decreased p-JNK levels while increasing IκB levels which may be the mechanism of TGP treatment. Our findings demonstrated that TGP treatment can ameliorate HFD-induced kidney injury via regulating JNK and IκB signals mediated by MyD88.