The function of hedgehog signaling has previously been shown to be crucial for craniofacial development. In this study, we treated C57/BL6J mice with the hedgehog pathway inhibitor vismodegib by oral gavage to establish a stable vismodegib-induced cleft palate model. At E10.5 and E12.5, mice in the experimental group were treated with 100 mg/kg of vismodegib, whereas mice in the control group were treated with solvent. The treated pregnant mice were sacrificed on E13.5, E14.5, E15.5, and E16.5. Palatal shelf growth was evaluated via histological and immunohistochemical analyses as well as palatal organ culture. Immunohistochemical staining was performed to examine the expression of osteogenic proteins in the palatal tissue. A high proportion of the mice administered 2 doses of 100 mg/kg of vismodegib displayed a cleft palate. Histologic examination revealed severely retarded palatal shelf growth and thickened epithelium in the experimental group. Vismodegib exposure induced complete cleft palate, which was attributed to a reduced cell proliferation rate in the palatal mesenchyme along the anterior-posterior axis. Moreover, this model also showed delayed ossification in the region of palatine bone with downregulation of Indian hedgehog (Ihh) protein. Our results suggest that vismodegib can be used to inhibit hedgehog signaling to affect palatal morphogenesis. Under treatment with this exogenous inhibitor, the cell proliferation rate of the palatal shelves and the osteogenic potential of the hard palate were decreased, which likely contributed to the complete cleft palate.