Abstract Aims Given the importance of inflammation in the onset and progression of diabetic cardiomyopathy, we investigated the potential protective effects of triptolide, an anti-inflammatory agent, in streptozotocin-induced diabetic rat model and in H9c2 rat cardiac cells exposed to high glucose. Methods and results Diabetic rats were treated with triptolide (100, 200, or 400 μg/kg/day respectively) for 6 weeks. At the end of this study, after cardiac function measurements were performed, rats were sacrificed and their hearts were harvested for further histologic and molecular biologic analysis. Enhanced activity and expression of nuclear factor-kappaB (NF-κB) p65 in diabetic hearts were associated with increased inflammatory response, as demonstrated by increased pro-inflammatory cytokines, cell adhesion molecules and invading inflammatory cells, as well as increased fibrosis, in line with impaired left ventricular function. Triptolide attenuated these morpho-functional alterations. Furthermore, triptolide (20 ng/ml) also attenuated high glucose-induced inflammation in H9c2 rat cardiac cells. Conclusion Our data demonstrate that anti-inflammatory effects of triptolide involving the NF-κB signaling pathway can improve left ventricular function under diabetic conditions, suggesting triptolide treatment might be beneficial in diabetic cardiomyopathy.