Objective To investigate the effect of Toutongning Capsule on brain-derived neurotrophic factor (BDNF), tyrosine kinase receptor B (TrkB) receptor, extracellular signal-regulated kinase (ERK), and phosphorylated cAMP-response element binding protein (p-CREB) in rats with migraine. Methods A total of 60 Sprague-Dawley (SD) rats were randomly divided into control group, model group, and Toutongning intervention group. Nitroglycerin-induced SD rat models of migraine were established using the Tassorelli Methods The behavioral changes of the rats were observed. After the fifth time of establishment of rat models, ELISA was used to measure BDNF level, and immunohistochemistry was used to detect the protein expression and localization of BDNF, TrkB, ERK, and p-CREB in the trigeminal ganglion of the rats.Results Ethological observation showed that rats in the model group and intervention group scratched their heads and climbed the cage frequently and had red ears, with the intervention group having a shorter duration and lower frequencies of scratching heads and climbing cage compared with the model group (P<0.05). The control group did not show the above behavioral changes. ELISA results showed that the model group had a higher serum BDNF level in the ictal and interictal periods than that of the intervention group in the same periods and that of the control group (P<0.05), showing no gender difference (P>0.05). Immunohistochemistry results showed that the model group had higher protein levels of BDNF, TrkB, p-ERK, and p-CREB in the trigeminal ganglion in the ictal and interictal periods than those of the intervention group in the same periods and those of the control group (P<0.05), showing no gender difference as well. (P>0.05).Conclusions Toutongning Capsule can prevent migraine through down-regulating the protein expression of BDNF, TrkB, ERK, and p-CREB.