Hematopoietic pre-B-cell leukemia transcription factor (PBX)-interacting protein (HPIP/PBXIP1) is a corepressor for the transcription factor PBX. Previous studies showed that HPIP is frequently overexpressed in many tumors. However, the role of HPIP in head-and-neck squamous cell carcinoma (HNSCC) has not yet been determined. Thus, we decided to investigate the effects and mechanisms of HPIP in HNSCC. Our results demonstrated that HPIP is highly expressed in human HNSCC cell lines and provides the first evidence that knockdown of HPIP obviously inhibits proliferation and migration/invasion in HNSCC cells in vitro, as well as inhibits tumor growth in vivo. Furthermore, knockdown of HPIP significantly inhibits the expression of p-PI3K and p-Akt in human HNSCC cells. In conclusion, our study demonstrated that knockdown of HPIP significantly inhibits the proliferation and migration/invasion of HNSCC cells by suppressing the PI3K/Akt signaling pathway. Therefore, HPIP may be a novel potential therapeutic target for the treatment of HNSCC.