Misregulation of hedgehog (Hh) signaling has been implicated in the pathogenesis of basal cell carcinoma (BCC) and medulloblastoma. Vismodegib, an orally bioavailable Hh signal pathway inhibitor targeting Smo, has been approved for the treatment of advanced BCC. However, acquired drug resistance to vismodegib induced by point mutation in Smo is emerging as a major problem to vismodegib treatment. In this study, we designed and synthesized a novel chimeric compound NL‐103, which comprises structural elements of Hh pathway inhibitor vismodegib, and histone deacetylase (HDAC) inhibitor vorinostat. NL‐103 simultaneously and significantly inhibited both HDACs and Hh pathway. Importantly, NL‐103, as well as vorinostat, effectively overcame vismodegib resistance induced by Smoothened point mutations. Moreover, NL‐103 and vorinostat, but not vismodegib, significantly downregulated the expression of Gli2 which plays an important role in Hh pathway. These results indicate that HDAC inhibitory activity is essential for NL‐103 to overcome vismodegib resistance and that dual inhibition of HDAC and Hh signaling pathway may be a rational strategy for overcoming vismodegib resistance. Our findings suggest that NL‐103 may be a promising compound for clinical development as a more effective Hh pathway inhibitor.