Recent research suggests that STEAP4, a metalloreductase , plays a crucial role in various types of tumorigeneses, especially in gastrointestinal cancers. However, few oncogenes have been reported in oral squamous cell carcinoma (OSCC). Therefore, this study aimed to explore the potential role of STEAP4 in OSCC. The expression level of STEAP4 in OSCC tissues and adjacent normal tissues, was detected using immunohistochemistry. Publicly available online tools were utilized to analyze the expression, prognostic significance, and related enriched pathways of STEAP4 in head and neck squamous cell carcinoma (HNSCC) and OSCC. The relationship between STEAP4 expression and clinicopathological parameters in OSCC patients was validated using the χ2 test and Fisher's exact probability test. STEAP4 exhibited low expression in both HNSCC and OSCC. Whereas the prognosis for HNSCC patients was favorable, OSCC patients had poor outcomes. Genetic variability analysis revealed no alterations in STEAP4 in OSCC, whereas gene amplification was observed in HNSCC, suggesting tumor heterogeneity in STEAP4 among these cancer types. STEAP4, as a risk factor associated with poor patient prognosis, shows tumor heterogeneity in OSCC patients, that is potentially related to genetic mutations or differences in histological distribution of oral mucosa. These findings indicate that STEAP4 could serve as an independent predictor for assessing the prognosis of OSCC patients.