As a type of head and neck squamous cell carcinoma (HNSCC), oral squamous cell carcinoma (OSCC) with high incidence and low survival rate. Frequent deletion of PTPRS has been found in the HNSCC. LncRNA HCG11 and miR-455-5p have been reported to take part in several cancer occurrences, in which miR-455-5p was found to be upregulated in the OSCC. However, the role of HCG11 in OSCC development is still unclear. Several co-transfection systems were established to explore the regulation of HCG11 on OSCC cells. Cell proliferation was evaluated by MTT assay, flow cytometry of cell cycle distribution, immunofluorescence of Ki67, and western blot assay. Dual luciferase reporter assay was performed to verify the binding effects of miR-455-5p on HCG11 and PTPRS. The role of HCG11 knockdown in OSCC cell growth was also confirmed by nude mouse tumorigenicity assay in vivo. Knockdown of HCG11 increased the OSCC cell proliferation, as evidenced by enhanced cell vitalities over time, increased G1/S transition and Ki67 levels. Besides, lncRNA HCG11 was showed to negatively regulate miR-455-5p and miR-455-5p targeted PTPRS directly to affect its downstream indicators, which can further modulate OSCC cell proliferation and growth. The results in vivo confirmed that HCG11 knockdown promoted OSCC cell growth. Therefore, lncRNA HCG11/miR-R-455-5p axis can be considered as an upstream signalling circuit of PTPRS to regulate its activity and downstream pathways to further influence the progression of OSCC. This finding may provide a novel RNA-based therapeutic target for OSCC treatment. © 2020 John Wiley & Sons, Ltd.