Background <p>Solute carrier family 8 member A1 antisense RNA 1 (SLC8A1-AS1) is a long non-coding RNA (lncRNA) that has been identified in recent years and is implicated in the progression of various cancers, including glioma and thyroid cancer. However, its role in oral squamous cell carcinoma (OSCC) remains poorly understood. The aim of this study is to investigate the function of SLC8A1-AS1 in OSCC and to explore its potential mechanisms of action.</p> Methods <p>The TCGA database was utilized to analyze the expression and prognostic significance of SLC8A1-AS1 in OSCC. QRT-PCR was employed to measure the gene expression levels of SLC8A1-AS1 and its target genes. CCK-8, EdU staining, wound healing, and Transwell assays were conducted to assess the effects of SLC8A1-AS1 on OSCC cells. Dual-luciferase reporter gene and RNA pull-down assays were performed to verify the interactions between SLC8A1-AS1 and its target genes. Student’s t-test or one-way analysis of variance (ANOVA) was applied for data analysis in this study.</p> Results <p>SLC8A1-AS1 was found to be downregulated in OSCC tissues and cell lines. Overexpression of SLC8A1-AS1 inhbited the proliferation, migration, and invasion of OSCC cells. Bioinformatics analyses predicted that miR-1305 is a target of SLC8A1-AS1, while ESRRG is a target of miR-1305. Furthermore, the inhibitory effects of SLC8A1-AS1 on the proliferation, migration, and invasion of OSCC cells were reversed by the introduction of miR-1305 mimics.</p> Conclusion <p>SLC8A1-AS1 inhibits the progression of OSCC by modulating the miR-1305/ESRRG axis.</p>