Long noncoding RNAs (lncRNAs) are critical for initiation and progression in various tumors. However, the role of lncRNAs in head and neck squamous carcinoma (HNSCC) remains largely unexplored. Cetuximab resistance is a major challenge for epidermal growth factor receptor (EGFR) targeted therapy for HNSCC. Besides tyrosine kinases mechanisms, little is known about cetuximab resistance regulation by lncRNAs. Here, we have characterized an oncogenic lncRNA, named lnc-RP11-499F3.2 which is associated with poor clinical survival, tumor proliferation and metastasis in HNSCC. We show RP11-499F3.2 is overexpressed in cetuximab-resistance patient-derived xenograft (PDX) tumors that progressed following cetuximab treatment. Mechanistically, RP11-499F3.2 functions as a competing endogenous RNA (ceRNA) for miR-6817 to maintain Wnt2B stability and promoting the downstream targets of Wnt/β-catenin pathway. Furthermore, treatment of cetuximab-resistant HNSCC with lnc-RP11-499F3.2 silencing or Wnt2B inhibitor can restore cetuximab response. Our findings illustrate the oncogenic role of lnc-RP11-499F3.2 and Wnt signaling with potential prognostic value and therapeutics for HNSCC with cetuximab resistance.