Head and neck squamous cell carcinoma (HNSCC) is the sixth most frequent cancer worldwide, comprising ∼50% of all malignancies in some developing nations. Our recent work identified protein kinase Cε (PKCε) as a critical and causative player in establishing an aggressive phenotype in HNSCC. In this study, we investigated the specificity and efficacy of HN1-PKCε, a novel bifunctional cancer cell homing, PKCε inhibitory peptide, as a treatment for HNSCC. HN1-PKCε peptide was designed by merging two separate technologies and synthesized as a capped peptide with two functional modules, HN1 (cancer cell homing) and PKCε (specific PKCε inhibitory), connected by a novel linker module. HN1-PKCε preferentially internalized into UMSCC1 and UMSCC36 cells, two HNSCC cell lines, in comparison with oral epithelial cells: 82.1% positive for UMSCC1 and 86.5% positive for UMSCC36 compared with 1.2% positive for oral epithelial cells. In addition, HN1-PKCε penetrated HNSCC cells in a dose- and time-dependent manner. Consistent with these in vitro observations, systemic injection of HN1-PKCε resulted in selective delivery of HN1-PKCε into UMSCC1 xenografts in nude mice. HN1-PKCε blocked the translocation of active PKCε in UMSCC1 cells, confirming HN1-PKCε as a PKCε inhibitor. HN1-PKCε inhibited cell invasion by 72 ± 2% (P < 0.001, n = 12) and cell motility by 56 ± 2% (P < 0.001, n = 5) in UMSCC1 cells. Moreover, in vivo bioluminescence imaging showed that HN1-PKCε significantly (83 ± 1% inhibition; P < 0.02) retards the growth of UMSCC1 xenografts in nude mice. Our work indicates that the bifunctional HN1-PKCε inhibitory peptide represents a promising novel therapeutic strategy for HNSCC.