The action and the latent mechanism of HNF1A-AS1 in oral squamous cell carcinoma (OSCC) development were probed. Levels of HNF1A-AS1, microRNA-138 (miR-138) and Cyclin-dependent kinase 6 (CDK6) were examined. In vitro assays were conducted using SCC-4 and SCC15 cells derived from a human SCC of the tongue of a 55-year-old male. In vivo assay was performed by establishing OSCC mouse models. An elevated HNF1A-AS1 was detected in OSCC, and down-expressed HNF1A-AS1 inhibited migration and invasion, and promoted apoptosis in OSCC cells in vitro. HNF1A-AS1 targeted miR-138 to positively regulate the expression of CDK6, a target of miR-138. Knockdown of miR-138 attenuated the action of HNF1A-AS1 silencing on OSCC cell malignant phenotypes. Besides that, overexpression of CDK6 weakened miR-138-mediated anti-cancer functions. Moreover, HNF1A-AS1 knockdown restrained OSCC growth in nude mice. HNF1A-AS1 promoted OSCC tumorigenesis via miR-138/CDK6 pathway, indicating the potential molecular contribution of HNF1A-AS1 on OSCC pathogenesis.