Epithelial-to-mesenchymal transition (EMT) is key to invasion and metastasis by oral squamous carcinoma (OSCC) cells. MicroRNAs (miRNAs) such as miRNA-146a are known to be upregulated in OSCC. However, it is unclear whether they are involved in driving EMT. Here, we investigated the effect of miR-146a overexpression on proliferation, migration, and EMT in OSCC cells. OSCC cells were transfected with a plasmid expressing miR-146a precursor. Cell lines that stably overexpressed miRNA-146a were assessed for proliferation, colony formation, and invasiveness in vitro. Expression of markers and regulators of EMT, cell motility, and invasion were measured by qRT-PCR and western blot. Potential miRNA-146a binding sites in the 3'UTR of ST8SIA4 were identified by bioinformatic analysis. To confirm that miRNA-146a binds to and regulates ST8SIA4, we transfected OSCC cell lines with miRNA-146a mimics and a luciferase reporter construct containing either the wild type or mutant 3'UTR of ST8SIA4. OSCC cell lines that overexpressed miR-146a displayed higher proliferation, colony formation, invasion, and MMP-2 activity than cells transfected with a control vector. Overexpression of miR-146a also decreased expression of the epithelial cell marker E-cadherin and increased expression of Twist1, a transcription factor that promotes EMT, as well as markers associated with mesenchymal cells (vimentin and N-cadherin) and tumor invasion (p-paxillin and p-cortactin). Luciferase expression was lower in OSCC cells transfected with miRNA-146a mimics or with luciferase constructs carrying the wild type, but not mutant, 3'UTR of ST8SIA4. Overexpression of miR-146a promotes EMT phenotypes and may drive tumorigenesis and progression in OSCC, making it a useful target for future OSCC treatments.