Mutations in components of the Hedgehog (HH) signal transduction pathway are found in the majority of basal cell carcinoma (BCC) and medulloblastoma incidents. Cancerous cells with intrinsic or acquired resistance to antagonists targeting the seven transmembrane effector Smoothened (SMO) frequently invoke alternative mechanisms for maintaining deviant activity of the GLI DNA binding proteins. Here we introduce a chemical agent that simultaneously achieves inhibition of SMO and GLI activity by direct targeting of the SMO heptahelical domain and the GLI-modifying enzymes belonging to the histone deacetylase (HDAC) family. We demonstrate a small molecule SMO-HDAC antagonist (IHR-SAHA) retains inhibitory activity for GLI transcription induced by SMO-dependent and -independent mechanisms frequently associated with cancer biogenesis. Synthetic combinatorial therapeutic agents such as IHR-SAHA that a priori disable cancer drivers and anticipated mechanisms of drug resistance could extend the duration of disease remission, and provide an alternative clinical development path for realizing combinatorial therapy modalities.