Heat-shock protein 90 (HSP90) is a major cellular chaperone protein. HSP90 supports the correct conformation, stabilization, activation, and localization of 'client' oncoproteins, many of which are involved in tumor progression. Therefore, the use of HSP90 inhibitors has become a new strategy in antitumor therapy. However, the effects of an HSP90 inhibitor on oral squamous cell carcinoma are still unclear. NVP-AUY922 (Novartis) is a novel 4,5-diaryloxazole adenosine triphosphate-binding site HSP90 inhibitor. In this study, we investigated the antitumor effect of novel HSP90 inhibitor NVP-AUY922 against oral squamous cell carcinoma. NVP-AUY922 inhibited the proliferation of oral squamous cell carcinoma cells in vitro. NVP-AUY922 caused degradation of client protein inducing ErbB2, p-Akt, p-S6, hypoxia-inducible factor 1-α (HIF1-α) and vascular endothelial growth factor (VEGF) and up-regulation of HSP70 in HSC-2 oral squamous cell carcinoma. NVP-AUY922 increased the expression of cleaved caspase-3 and induced apoptosis in HSC-2 cells. Treatment of NVP-AUY922 induced a robust antitumor response and suppressed p-Akt and VEGF expression in an HSC-2 xenograft model. In summary, NVP-AUY922 exhibits in vitro and in vivo efficiency against oral squamous cell carcinoma, representing a promising therapeutic approach for oral squamous cell carcinoma.