This study attempted to investigate possible molecular mechanism and role of miR-18a-5p in head and neck squamous cell carcinoma (HNSCC). Differential miRNAs and their possible targets were analyzed through TCGA database. By conducting qRT-PCR, miR-18a-5p was tested to be increased and SORBS2 was assessed to be downregulated in HNSCC cells. CCK-8, Transwell, and flow cytometry assays disclosed that miR-18a-5p facilitated HNSCC cell proliferation, migration, and invasion and repressed cell apoptosis. By dual-luciferase reporter gene assay, it was verified that miR-18a-5p had binding sites into SORBS2. Rescue experiments displayed that forced expression of SORBS2 restored the impact of miR-18a-5p overexpression on HNSCC cells. Collectively, our research preliminarily identified the promotion effect of miR-18a-5p/SORBS2 axis on malignant phenotypes of HNSCC cells. Our findings may provide a preclinical reference for HNSCC treatment.