Diabetic encephalopathy (DE) is a serious complication of diabetes, which affects patients' quality of life. We aimed to explore HLJDD in the treatment of DE by LC-MS and bioinformatics. UPLC-Q Exactive-Orbitrap MS was employed to clarify the compounds. The modules and hub targets of DE were gained from a weighted gene co-expression network analysis (WGCNA). Subsequently, an Herb-Compound-Target network was constructed and enrichment analysis was used. In addition, a protein-protein interaction (PPI) network was constructed and molecular docking was used to verify the above analysis. As result, 138 compounds and 10 prototypes in brain were identified. In network pharmacology, 8 modules and 5692 hub targets were obtained from WGCNA. An Herb-Compound-Target network was constructed by 4 herbs, 10 compounds and 56 targets. The enrichment analysis showed that the treatment of DE with HLJDD involve oxidative stress and neuroprotection. Beside, SRC, JUN, STAT3, MAPK1 and PIK3R1 were identified and as hub targets of HLJDD in treating DE. Moreover, Molecular docking showed that five hub targets had strong affinity with the corresponding alkaloids. Therefore, we explored the underlying mechanisms of HLJDD in the treatment of DE and to provide the theoretical and scientific basis for subsequent experimental studies and clinical applications.© 2023 Wiley-VCH GmbH.