The present study describes the preparation of a dodecapeptide YHWYGYTPQNVI (GE11)‑conjugated liposome bound with polyethylene glycol to enhance the therapeutic effect of resveratrol (RSV) in head and neck cancer cells. The results indicated that (RSV)‑loaded GE11‑conjugated liposomes (RSV‑GL) exhibited a high entrapment efficiency of >95%, with an active drug loading level of 19.5% w/w. Release kinetics revealed that RSV was released in a slow and sustained manner from the RSV‑GL and RSV‑loaded liposome (RSV‑L) nanoparticulate systems. The epidermal growth factor receptor (EGFR)‑overexpressing squamous cell carcinoma HN cells specifically internalized GE11 surface‑conjugated liposome in a manner that was markedly increased compared with that of the non‑targeted carrier. Consistently, RSV‑GL exhibited a significantly increased cytotoxic effect compared with that of the non‑targeted nanoparticles. Notably, RSV‑GL induced significantly increased proportions of early (~60%) and late (~10%) apoptotic cells in head and neck cancer cell populations. To the best of our knowledge, the application and development of EGFR‑targeted peptide‑conjugated liposome system for RSV delivery has not been studied previously in the treatment of head and neck cancer. In addition, RSV‑GL exhibited the greatest antitumor efficacy compared with any other group. RSV‑GL exhibited a 2‑fold decrease in tumor volume compared with the free RSV and a 3‑fold decrease in volume compared with the control. Overall, the nanomedicine strategy described in the present study may potentially advance the chemotherapy‑based treatment of head and neck cancer, with promising applications in other EGFR‑overexpressing tumors.