Isobavachalcone (ISO) exhibits good anti‐inflammatory activity. We evaluated the renoprotective effects of ISO against diabetic nephropathy (DN). Diabetic rats established by the single injection of streptozotocin (STZ) were orally treated with ISO. The levels of serum creatinine (Scr), blood urea nitrogen (BUN), and 24 hr urinary protein were measured. In this study, ISO effectively ameliorated renal damage by reducing BUN, Scr, and 24 hr urinary protein and also improved kidney pathological appearances. ISO prevented STZ‐caused apoptosis in the glomerular tissue in vivo and blocked the high glucose (HG)‐induced growth inhibitory effect in human renal glomerular endothelial cells in vitro. Moreover, ISO reduced pro‐inflammatory mediator production and blocked the NF‐κB pathway in the damaged renal tissues and HG‐treated HRGEC cells. Taken together, the results of this study indicate that ISO consumption might have significant beneficial effects on the DN and this action might be correlated with the modulation of the NF‐κB pathway. Practical applications ISO is an active compound from the dried ripe fruit of Psoralea corylifolia L. seed, which is traditionally served as a food ingredient in Asia. In this investigation, we observed the beneficial effects of ISO on a murine model with DN. Further research revealed that the protective action of ISO might be connected with its weak hypoglycaemic and notable anti‐inflammatory effects. Our research data suggest that ISO‐enriched food might be a good choice for people suffering from DN.