Oral squamous cell carcinoma (OSCC) is one of the most common types of cancer worldwide. Accumulating evidence has shown that long noncoding RNAs (lncRNAs) serve important roles in the development of OSCC. The purpose of this study was to investigate the biological function and underlying regulatory mechanism of lncRNA homeobox A cluster antisense RNA2 (HOXA-AS2) in OSCC. RT-qPCR was performed to analyze the HOXA-AS2 expressions in human immortalized oral epithelial cell (HIOEC) line, human OSCC cell lines, and plasma. The expression of HOXA-AS2 and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) in Tca-8113 cells were knocked down or overexpressed by transfection with shRNA-HOXA-AS2 or pcDNA-EZH2, respectively. The interaction between HOXA-AS2 and EZH2 was validated by RNA immunoprecipitation assay. In addition, cell proliferation was assessed by CCK-8 and EdU assays. Cell cycle distribution was analyzed by flow cytometry. Cell migration and invasion were detected using wound healing and Transwell assays, respectively. Apoptosis was detected by TUNEL staining. The protein expression levels of cell cycle and apoptosis-related proteins were measured by western blot analysis. Compared with HIOEC cells, HOXA-AS2 expression in OSCC cells was upregulated. HOXA-AS2 knockdown significantly inhibited Tca-8113 cell proliferation, blocked the cell cycle by arresting cells in the G0/G1 phase, promoted apoptosis, and suppressed migration and invasion. In addition, HOXA-AS2 was predicted to directly target EZH2 and positively regulate EZH2 expression. EZH2 overexpression could reverse the inhibitory effect of HOXA-AS2 knockdown on the proliferation, migration, and invasion of Tca-8113 cells. In summary, the findings suggested that HOXA-AS2 may inhibit cell proliferation, invasion, and migration, induce cell cycle arrest in the G0/G1 phase, and increase cell apoptosis by targeting EZH2. The research indicated that HOXA-AS2/EZH2 axis may play a key role in the development of OSCC.