Diabetic nephropathy, a major diabetes complication, is often exacerbated by glucolipotoxicity. The potential benefits of mulberry leaf extract (MLE) and its primary component, neochlorogenic acid (nCGA), in combating this condition have not been extensively explored. High-fat diet-fed db/db mice were employed as a model for glucolipotoxicity-induced diabetic nephropathy. The mice were treated with MLE or nCGA, and their body weight, insulin sensitivity, blood lipid profiles, and kidney function were assessed. In addition, modulation of the JAK-STAT, pAKT, Ras, and NF-κB signaling pathways by MLE and nCGA was evaluated. MLE and nCGA did not significantly decrease blood glucose level but effectively mitigated the adverse effects of a high-fat diet on blood lipid profile and kidney function. Improvements in body weight, insulin sensitivity, and kidney structure, along with a reduction in fibrosis, were observed. Both MLE and nCGA regulated lipid metabolism abnormalities, significantly inhibited the accumulation of glycosylated substances in glomeruli, and modulated crucial signaling pathways involved in diabetic nephropathy. Although they do not directly affect blood glucose level, MLE and nCGA show significant potential in managing glucolipotoxicity-induced diabetic nephropathy by targeting lipid metabolism and key molecular pathways. The present findings suggest MLE and nCGA may be promising therapeutic agents for diabetic nephropathy, and further exploration in human patients is warranted.