〔Abstract〕 Abstract Objective To investigate the molecular mechanisms and pathways of action of total flavonoids of Draco- cephalum moldavica L. (TFDM) in treating vascular cognitive impairment ( VCI) based on network pharmacology and in vivo animal experiments . Methods The swiss target prediction database , literature , and PubChem were used to screen the active components and action targets of TFDM . The online mendelian inheritance in man ( OMIM) and GeneCards databases were utilized to screen for possible VCI targets . Venny software was used to ob- tain the intersection target of TFDM and VCI . The search tool for recurring instances of neighbouring genes (String) database and Cytoscape software was used to construct the PPI network . The database for annotation , vi- sualization and integrated discovery (DAVID) database was utilized to screen for the kyoto encyclopedia of genes and genomes (KEGG) pathway and gene ontology (GO) enrichment analyses to explore the molecular mechanism and signaling pathway of TFDM for VCI . 24 rats were divided into Sham , Model , Donepezil , and TFDM groups . Except for the Sham group , the VCI model was created using modified bilateral common carotid artery ligation . Af- ter continuous gavage for 21 days , the Morris water maze test was used to evaluate the spatial learning and memory ability of rats . Hematoxy-lineosin (HE) staining was used to observe the pathological changes in the hippocampal CA1 and cortex region of the animals and immunohistochemistry detection of zonula occludens-1(ZO-1) content in the brains of the rats . Western blot was used to detect nuclear factor kappa-B p65 (NF-κB p65) and tumor necro- sis factor-α(TNF-α) in rat brains . Results A total of 39 active ingredients of TFDM were screened , 209 corre- sponding targets , 10 417 gene targets of VCI , and 193 intersecting targets . According to the results of the GO en- richment of function analysis , TFDM could improve the response of reactive oxygen species and metabolic processes of reactive oxygen species , etc . KEGG pathway enrichment analysis suggested that TFDM might regulate TNF , IL- 17 signing pathway , etc . The results of animal experiments showed that TFDM improved learning and memory while reduced pathological damage in the brains of VCI rats . In addition , TFDM upregulated the positive expression of ZO-1 and downregulated the protein levels of TNF-αand NF-κB p65 ( P < 0. 05 ) . Conclusion TFDM can improve the cognitive function of VCI through multi-components and multi-targets , and its key mechanism may be related to inhibiting TNF-α/NF-κB p65 signaling pathway , reducing neuroinflammation , and improvement of blood- brain barrier permeability.