Background <p>Head and neck squamous cell carcinoma (HNSCC) demonstrates insidious onset, high prevalence, and low 5-year overall survival rate. While downregulation of miR-493-5p is implicated in the development of various cancers, its role in HNSCC remains unclear. Here, we explored the association of miR-493-5p with HNSCC progression and elucidated the underlying mechanisms.</p> Methods <p>The miR-493-5p expression in HNSCC tissues and cells was verified by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cell proliferation and migration were detected by Cell Counting Kit 8, colony formation, and wound-healing assay. Dual-luciferase reporter gene assay was used to verify that miR-493-5p targeted hypoxia-inducible factor (HIF)-1α. Cobalt chloride (CoCl₂) was used to induce HIF-1α expression to perform rescue assays. SCC VII cells were used to construct the mouse model. After 15&#xa0;days, the tumour volume was compared. The expression of HIF-1α, glycolysis, and epithelial–mesenchymal transition (EMT) proteins were verified by western blotting.</p> Results <p>MiR-493-5p expression was low and beneficial to prognosis in HNSCC tumours. MiR-493-5p constrained HNSCC cell proliferation and migration and inhibited HIF-1α expression by targeting its 3′ untranslated region directly. CoCl₂ addition reduced miR-493-5p-induced cell proliferation, which may be related to the increased expression of HIF-1α. MiR-493-5p decelerated tumour cell growth in mice and was associated with glycolysis and EMT in HNSCC cells.</p> Conclusions <p>MiR-493-5p, which targets HIF-1α and inhibits glycolysis and EMT, may be a novel therapeutic target for HNSCC.</p>