The efficacy of bevacizumab plus cetuximab-based chemotherapy remains unclear in head and neck squamous cell carcinoma (HNSCC). The aim of this study was to investigate the anticancer efficacy of a bevacizumab-cetuximab-cisplatin triple-agent combination in treating mouse HNSCC. SCC-VII tumor-bearing C3H mice were treated with bevacizumab, cetuximab and cisplatin either alone or in various combinations. In vivo results showed that the largest delay in tumor growth and the maximum increase in survival were not in the triple-agent combination therapy, but in the bevacizumab plus cisplatin therapy. TUNEL assay showed that the apoptosis indices in bevacizumab plus cisplatin group and a triple-agent combination group were 31.6 ± 12.0% and 6.9 ± 1.3%, respectively. Western blot showed that down-regulation of Bcl-2 and up-regulation of cleaved caspase-3 contributed to the anticancer effect of a triple-agent combination and bevacizumab plus cisplatin. Moreover, the maximum level of cleaved caspase-3 expression was not found in the triple-agent combination group but in the bevacizumab plus cisplatin group. Bevacizumab plus cisplatin therapy is better than bevacizumab-cetuximab-cisplatin triple therapy in the mouse HNSCC model. Our findings suggest that the bevacizumab-cetuximab-cisplatin regimen may not be suitable for treating HNSCC.