Ethnopharmacological relevance: Glaucocalyxin B (GLB) is known for its anti-inflammatory properties, including alleviating neuroinflammation and treating inflammatory bone injuries. However, its effects on inflammation-induced damage in diabetic cardiomyopathy (DCM) have not been adequately studied. Aim of the study: This study aims to investigate the effects of GLB on inflammatory injury in DCM and to explore its mechanisms in reducing myocardial inflammatory injury. Materials and methods: We utilized network pharmacology analysis, a diabetic rat model (the experimental period lasts for 8 weeks), and H9c2 rat cardiomyocyte experiments to assess the potential of GLB to alleviate DCM-induced inflammatory damage, while also investigating the related anti-inflammatory mechanisms of GLB. Results: Network pharmacology analysis of GLB revealed its involvement in regulating myocardial cell proliferation and the DCM process, as well as its association with inflammation, apoptosis, and oxidative damage. Further in vivo and in vitro studies demonstrated that the application of GLB significantly reduced the levels of oxidative stress markers, such as ROS and MDA, at both tissue and cellular levels. Additionally, GLB also reduced cardiomyocyte apoptosis caused by high glucose levels by enhancing the BCL2/BAX ratio. Signal pathway analysis indicates that the use of GLB inhibits the activation of the NF-κB/NLRP3 pathway. Conclusion: Overall, the findings suggest that GLB effectively mitigates oxidative stress and inflammatory damage associated with DCM. The protective effects of GLB are linked to its modulation of the NF-κB/NLRP3 signaling pathway.