ObjectiveTo study the mechanism of Mahuang Xixin Fuzitang （MXFT） against migraine. MethodTraditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP）， SiwssTargetPrediction and other databases were used to screen the active components and action targets of MXFT as well as migraine-related targets. The potential protein-protein interaction （PPI） network diagram was plotted for the intersection targets of MXFT and migraine using STRING 11.5. Metascape was used for Gene Ontology （GO） and Kyoto Encyclopedia of Genes and Genomes （KEGG） enrichment analysis of potential intersection targets. The component-target-pathway network of MXFT was constructed by Cytoscape 3.7.1 to screen core targets with high degree value. Finally， the binding strength between core target and its mapping components was verified by molecular docking， and the core targets with desirable docking results were verified by animal experiments in vivo. Forty eight SD rats were selected， and except the blank group， the other rats were subcutaneously injected with nitroglycerin to prepare the migraine rat model. The modeled rats were randomly divided into model group， positive drug group and MXFT high-， medium- and low-dose groups. The positive drug group was given zolmitriptan tablets， and the MXFT high-， medium- and low-dose groups were given high， medium and low doses of MXFT， respectively. The changes of behavior and pain threshold of rats in each group were observed every other day after modeling. The levels of calcitonin gene-related peptide （CGRP）， extracellular signal-regulated kinase 2 （ERK2） and c-fos proto-oncogene （FOS） protein in plasma were detected by enzyme-linked immunosorbent assay （ELISA）. Immunohistochemical technique and Western blot were employed to determine the levels of extracellular signal-regulated kinase 1/2 （ERK1/2， also known as MAPK1/3） and protein kinase B 1 （Akt1）， protein kinase C α （PRKCA） in trigeminal nerve of SD rats. ResultThe network pharmacology showed that the core targets of MXFT in the treatment of migraine were MAPK1， MAPK3， Akt1， PRKCA， etc.， mainly involving neuroactive ligand-receptor interaction signaling pathway， calcium signaling pathway， MAPK signaling pathway， etc. The molecular docking demonstrated that MAPK1， MAPK3， Akt1， PRKCA， PRKCB and PRKCG had good binding ability with their mapping components. The animal experiments indicated that compared with the conditions in the blank group， the number of head scratching in the model group was increased （P<0.01）， and the pain threshold was decreased （P<0.01）. Compared with the conditions in the model group， the number of head scratching in each administration group was reduced （P<0.01）， and the pain threshold was increased （P<0.01）. In addition， the levels of CGRP， ERK2 and FOS proteins in plasma， and Akt1， ERK1/2 and PRKCA proteins in trigeminal ganglion of the model group were higher than those of the blank group （P<0.05， P<0.01）. The levels of CGRP， ERK2 and FOS proteins in plasma and Akt1， ERK1/2 and PRKCA proteins in trigeminal ganglion of each administration group were lower than those of the model group （P<0.05， P<0.01）. ConclusionMXFT had multi-component， multi-target and multi-pathway characteristics in the treatment of migraine， and the mechanism might be related to inhibiting vasodilation， reducing the release of inflammatory factors and inhibiting neuronal hyperactivity.