Ergosterol (ERG) was reported to exhibit anti-inflammatory and anti-oxidative activities. Besides, ERG was found to attenuate kidney injury in the diabetic mouse. However, the protective effect of ERG in diabetic nephropathy-induced inflammation remains unclear. We aimed to study whether ERG could alleviate diabetic nephropathy-induced inflammation and explore the underlying mechanisms. The diabetic nephropathy mice model was induced by intraperitoneal injection of 30 mg/kg Streptozotocin (STZ). The inflammatory cytokines levels, and insulin concentration in the serum of both diabetic nephropathy patients and mouse model were determined by ELISA. mRNA and protein expression were analyzed by RT-PCR and Western blot, respectively. Fasting blood glucose levels were detected using a commercial kit. Blood biochemistry levels were determined by an automatic analyzer. Mesangium proliferation was detected by PAS staining. It was found that serum levels of IL-6, TNF-α, and MCP-1 dramatically increased in the diabetic nephropathy patients. In mice, ERG treatment greatly decreased fasting blood glucose levels, inflammatory cytokine levels, and renal injury, while it enhanced the insulin level. Mechanically, ERG treatment dramatically decreased NF-κB signaling pathway. Our findings highlight the potential of ERG as an effective agent to treat diabetic nephropathy.