Objective:To explore the protective effect of Zhengtian pill on migraine rats and its possible mechanism. MethodsRats were divided into control group (0.9% NaCl solution), model group (0.9% NaCl solution), Zhengtian pill group (1.62 g/kg), protein kinase C (PKC) agonist group (2 mg/kg TPPB), Zhengtian pill + TPPB group (1.62 g/kg Zhengtian pill + 2 mg/kg TPPB), with 12 rats in each group. Migraine rat model was established by nitroglycerin injection. The occurrence time and disappearance time of ear flush and the numbers of crawling cage and scratching head in different time periods were recorded after the model was established. HE staining was used to observe the morphological changes of nerve cells in brain tissue. The levels of TNF-α, IL-6 and CINC-1 in serum were detected by ELISA. The levels of calcitonin gene-related peptide (CGRP) and 5-hydroxytryptamine (5-HT) in brain homogenate were measured by radioimmunoassay, and the expressions of PKC and P2X3 proteins in brain tissue were detected by Western blot.  Results:①Compared with the control group, the numbers of head scratching and cage climbing in 0-45 min, 45-75 min, 75-120 min increased in the model group, the levels of serum TNF-α, IL-6 and CINC-1 increased, the level of CGRP in brain tissue increased, the level of 5-HT decreased, and the expressions of PKC and P2X3 proteins increased in the model group (P<0.05). ②Compared with the model group, the numbers of head scratching and cage climbing in Zhengtian pill group decreased significantly, the occurrence time of ear flush was significantly prolonged, the disappearance time of ear flush was significantly shortened, the levels of TNF-α, IL-6 and CINC-1 decreased, the level of CGRP decreased, the level of 5-HT increased, and the expressions of PKC and P2X3 proteins decreased (P<0.05). In the TPPB group, the numbers of head scratching and cage climbing increased, the occurrence time of ear flush was significantly shortened, the disappearance time of ear flush was significantly prolonged, the levels of serum TNF-α, IL-6 and CINC-1 increased, the level of CGRP in brain tissue increased, the level of 5-HT decreased, and the expressions of PKC and P2X3 proteins increased (P<0.05). In Zhengtian pill + TPPB group, the numbers of head scratching and cage climbing, the disappearance time of ear flush, the levels of TNF-α, IL-6, CINC-1 in serum and CGRP in brain tissue, and the expressions of PKC and P2X3 proteins were lower than those in TPPB group, while the level of 5-HT was higher and the occurrence time of ear flush was longer than those in TPPB group (P<0.05).  Conclusion:Zhengtian pill can alleviate nerve cell injury and headache in migraine rats, and the effect may be achieved by inhibiting the PKC/P2X3 pathway.