Topiramate is an anti-epileptic drug that is commonly prescribed not just to prevent seizures but also migraine headaches, with over 8 million prescriptions dispensed annually. Topiramate use during pregnancy has been linked to significantly increased risk of babies born with orofacial clefts (OFCs). However, the exact molecular mechanism of topiramate teratogenicity is unknown. In this study, we first used an unbiased antibody array analysis to test the effect of topiramate on human embryonic palatal mesenchyme (HEPM) cells. This analysis identified 40 differentially expressed proteins, showing strong connectivity to known genes associated with orofacial clefts. However, among known OFC genes, only TGFβ1 was significantly upregulated in the antibody array analysis. Next, we validated that topiramate could increase expression of TGFβ1 and of downstream target phospho-SMAD2 in primary mouse embryonic palatal mesenchyme (MEPM) cells. Furthermore, we showed that topiramate treatment of primary MEPM cells increased expression of SOX9. SOX9 overexpression in chondrocytes is known to cause cleft palate in mouse. We propose that topiramate mediates upregulation of TGFβ1 signaling through activation of γ-aminobutyric acid (GABA) receptors in the palate. TGFβ1 and SOX9 play critical roles in orofacial morphogenesis, and their abnormal overexpression provides a plausible etiologic molecular mechanism for the teratogenic effects of topiramate.