Aberrant long non-coding RNA (lncRNA) expression contributes cancer development and resistance to therapy. This study first assessed expression of lncRNA LINC00958 in a variety of human cancers using GEPIA database data and then associated it with prognosis of head and neck squamous cell carcinoma (HNSCC) and investigated LINC00958 interaction with c-Myc and the c-Myc-related gene interplay in HNSCC cells.A cohort of 48 HNSCC vs normal tissues was collected for qRT-PCR analysis of LINC00958 and c-Myc expression and statistical analyses. HNSCC cell lines were subjected to transfection with LINC00958 and c-Myc siRNAs or cDNA and their negative control siRNA or empty vector for qRT-PCR, Western blot, cell viability, colony formation, luciferase reporter, chromatin immunoprecipitation, and RNA immunoprecipitation assays.The data showed that LINC00958 expression was upregulated in HNSCC tissues and cell lines, upregulation of which was associated with poor tumor differentiation, advanced tumor stage, and shorter overall survival of patients. In vitro, LINC00958 expression induced HNSCC cell viability and colony formation, whereas knockdown of LINC00958 expression enhanced HNSCC cell sensitivity to ionizing radiation and cisplatin treatment. Mechanistically, LINC00958 is a direct target of c-Myc and can enhance the transcriptional activity of c-Myc, thus to form a positive feedback gene network in HNSCC cells, and in turn to modulate HNSCC cell resistance to chemo- and radiotherapy.This study demonstrated the LINC00958 interplay with c-Myc as a feedback loop facilitated HNSCC development and resistance to chemo- and radiotherapy. Targeting of such a network could be further evaluated as a novel therapeutic strategy for HNSCC patients.