Oral squamous cell carcinoma (OSCC) represents the primary subtype of head and neck squamous cell carcinoma (HNSCC), characterized by a high morbidity and mortality rate. Although previous studies have established specific correlations between euchromatic histone lysine methyltransferase 2 (EHMT2), a histone lysine methyltransferase, and the malignant phenotype of OSCC cells, its biological functions in OSCC remain largely unknown. This study, grounded in bioinformatics predictions, aims to clarify the influence of EHMT2 on the malignant behavior of OSCC cells and delve into the underlying mechanisms. EHMT2 exhibited high expression in OSCC tissues and demonstrated an association with poor patient outcomes. Artificial EHMT2 silencing in OSCC cells, achieved through lentiviral vector infection, significantly inhibited colony formation, migration, invasion, and cell survival. Regarding the mechanism, EHMT2 was found to bind the promoter of arrestin beta 1 (ARRB1), thereby suppressing its transcription through H3K9me2 modification. ARRB1, in turn, was identified as a negative regulator of the Hedgehog pathway, leading to a reduction in the proteins GLI1 and PTCH1. Cancer stem cells (CSCs) were enriched through repeated sphere formation assays in two OSCC cell lines. EHMT2 was found to activate the Hedgehog pathway, thus promoting sphere formation, migration and invasion, survival, and tumorigenic activity of the OSCC-CSCs. Notably, these effects were counteracted by the additional overexpression of ARRB1. In conclusion, this study provides novel evidence suggesting that EHMT2 plays specific roles in enhancing stem cell properties in OSCC by modulating the ARRB1-Hedgehog signaling cascade.