Objective The aim of the present study was to investigate the roles and molecular mechanism of long non-coding RNA (lncRNA) HOXA-AS3 in the progression of oral squamous cell carcinoma (OSCC). Methods The expression of HOXA-AS3 and miR-218-5p was detected in OSCC tissues and cells using quantitative real-time polymerase chain reaction (qRT-PCR). Cell Counting Kit-8 (CCK-8) and colony formation assays were used to examine the effects of HOXA-AS3 and miR-218-5p on the proliferation of OSCC cells. Luciferase reporter gene assay was used to confirm the directly binding condition between lncRNA HOXA-AS3 and miR-218-5p in OSCC cells. RNA immunoprecipitation assay was employed to verify the interaction between HOXA-AS3 and miR-218-5p. Results The relative expression of lncRNA HOXA-AS3 was observably upregulated in OSCC tissues and cell lines compared with the para-cancerous tissues and normal human oral keratinocyte (NHOK), respectively. Knockdown of HOXA-AS3 significantly inhibited the proliferation and colony formation of OSCC cells. Bioinformatics analysis and luciferase reporter assay showed that HOXA-AS3 directly bound to miR-218-5p. Moreover, the expression of miR-218-5p was negatively regulated by HOXA-AS3, and there was an inverse correlation between them. Silencing miR-218-5p reversed the inhibitory effect of lncRNA HOXA-AS3 knockdown on the proliferative potential of OSCC cells. Conclusion In summary, our study illustrated lncRNA HOXA-AS3 promoted cancer cell proliferation in OSCC possibly by sponging miR-218-5p for the first time, which provides a new target or a potential diagnostic biomarker of the treatment for OSCC.