Objective To investigate the effects of targeted inhibition of Derlin-1 expression on apoptosis and paclitaxel sensitivity of head and neck squamous cell carcinoma (HNSCC) cells. Methods Using HNSCC cell lines (FADU, TU686, CAL27) as the study subjects. The shRNA-Derlin-1 plasmids were constructed and transfected into the cells. After treating the cells with paclitaxel, the apoptosis rate was detected by flow cytometry. Results The shRNA-Derlin-1 plasmid significantly inhibited the expression of Derlin-1 in HNSCC, reduced the phosphorylation level of tumor cell protein kinase B (AKT) and the expression of B-cell lymphoma-2 (Bcl-2), and significantly increased the apoptosis rate of HNSCC (P<0.001). After paclitaxel treatment, the apoptosis rate of HNSCC was further increased (P<0.001). Conclusions Targeted inhibition of Derlin-1 can promote tumor cell apoptosis by blocking the AKT pathway activation and down-regulating Bcl2 expression, thereby increasing the sensitivity of HNSCC to paclitaxel.