Objective: To investigate the efficacy and possible mechanism of Yougui Pill in the treatment of hormone-resistant nephrotic syndrome. Methods: 60 Wisar rats were randomly divided into control group, model group (preparation of adriamycin by one-off tail vein injection), prednisone treatment group (6.3 mg kg-1), prednisone combined with Yougui Pill low (TL, 6.3/2.8 mg kg-1), medium (TM, 6.3/5.6 mg kg-1), high (TH, 6.3/11.6 mg kg-1) dose treatment groups, with 10 rats in each group. The rats were administered continuously for 6 weeks. The body weight and 24-hour urinary protein content of rats were measured at 2, 4 and 6 weeks after administration, after the last administration, blood lipid and renal function were measured, HE, Masson and PAS staining were used to observe the pathological changes of rat kidney, Tunel staining was used to observe the apoptosis of rat kidney cells, and the expressions of JNK/p38 signaling pathway and apoptosis-related proteins in kidney tissues were detected by Western blot. Results: Two rats died in Model group and one rat died in TL and Prednisone groups respectively. The weight of model group decreased after 2 weeks of administration, after 4 and 6 weeks of administration, compared with Model group and Prednisone group, the weight of hormone and Yougui Pill combined treatment groups increased (P < 0.05). Compared with the control group, the 24-hour urinary protein increased, the levels of TP and ALB decreased, the levels of TC, TG, Scr and BUN increased, the glomerulosclerosis score, tubulointerstitial injury score, collagen fibers ratio increased, the apoptotic rate of renal cells increased, the phosphorylation levels of JNK and p38 protein increased, the expressions of Caspase-3 and Bax proteins increased in the model group, and the expression of Bcl-2 protein decreased (P < 0.05). Compared with the control group, the 24-hour urinary protein decreased, the levels of TP and ALB increased, the levels of TC, TG, Scr and BUN decreased, the glomerulosclerosis score, tubulointerstitial injury score, collagen fibers ratio decreased, the apoptotic rate of renal cells decreased, the phosphorylation levels of JNK and p38 protein decreased, the expressions of Caspase-3 and Bax proteins decreased in the model group, and the expression of Bcl-2 protein increased (P < 0.05). Conclusions: Yougui Pill can alleviate renal tissue damage and protect renal function in SRNS rats, which may be related to Yougui Pill inhibiting JNK/p38 signaling pathway and reducing renal cell apoptosis.