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OBJECTIVE In the present study, we aimed to explore lncRNA HOXD cluster antisense RNA 1 (HOXD-AS1) expression in oral squamous cell carcinoma (OSCC) tissues, its biological roles, and the underlying potential mechanisms in OSCC progression. MATERIALS AND METHODS HOXD-AS1 expression in paired OSCC and non-tumor tissues from 60 OSCC patients was determined by RT-qPCR. The effects of HOXD-AS1 and miR-203a-5p overexpression on expression of Annexin A4, a validated target of miR-203a-5p, were analyzed by RT-qPCR and Western blot. The roles of HOXD-AS1, miR-203a-5p and Annexin A4 in the invasion and migration of OSCC cells were analyzed by Transwell assays. RESULTS HOXD-AS1 overexpression in OSCC predicted poor survival. HOXD-AS1 was predicted to interact with miR-203a-5p, but its expression was not significantly correlated with miR-203a-5p. HOXD-AS1 overexpression increased Annexin A4 expression, while miR-203a-5p overexpression decreased Annexin A4 expression in OSCC cells. Transwell assays showed that invasion and migration of OSCC cells were enhanced by HOXD-AS1 and Annexin A4 overexpression but were reduced by miR-203a-5p overexpression. In addition, miR-203a-5p overexpression suppressed the role of HOXD-AS1 in cell movement and Annexin A4 expression. CONCLUSIONS HOXD-AS1 may upregulate Annexin A4 by sponging miR-203a-5p in OSCC to promote cancer cell invasion and migration.