Long non-coding RNA (lncRNA) actin filament-associated protein 1 antisense RNA 1 (AFAP1-AS1) has been reported to serve important roles in multiple types of cancer. However, the biological function and underlying mechanism of AFAP1-AS1 in oral squamous cell carcinoma (OSCC) remain largely unknown. The present study aimed to investigate the biological roles and clarify the potential mechanism of AFAP1-AS1 in OSCC. The expression levels of AFAP1-AS1 in OSCC tissues and cells were determined using reverse transcription-quantitative PCR. Cell proliferation, colony formation, migration and invasion were analyzed using Cell Counting Kit-8, colony formation, wound healing and Transwell invasion assays, respectively. The potential binding between AFAP1-AS1 and microRNA (miR)-145 was validated using dual luciferase reporter and RNA pull-down assays. A xenograft tumor model was established to evaluate the effect of AFAP1-AS1 in vivo. The results revealed that AFAP1-AS1 expression levels were markedly upregulated in OSCC tissues and cells. In addition, patients with OSCC with high expression levels of AFAP1-AS1 had a poor prognosis. Functionally, the knockdown of AFAP1-AS1 in OSCC cells significantly inhibited cell proliferation, migration and invasion in vitro. Similarly, in vivo AFAP1-AS1 knockdown prevented tumor growth and reduced tumor size and weight. Mechanistically, AFAP1-AS1 was discovered to regulate the expression levels of Homeobox A1 (HOXA1) by competing with miR-145. The inhibition of miR-145 partially attenuated the inhibitory effects of AFAP1-AS1 knockdown on OSCC cells. In conclusion, the findings of the present study suggested that AFAP1-AS1 may promote the progression of OSCC by regulating the miR-145/HOXA1 axis.