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Background/Objectives: Hypoxia-inducible factor 1-alpha (HIF-1α) is a transcription factor that escapes proteasomal degradation under hypoxic conditions, translocates to the nucleus, and activates genes involved in anaerobic glycolysis (e.g., GLUT1 and LDH-A) and vascular endothelial growth factor (VEGF) expression. Through its role in tumor progression, angiogenesis, and metabolic reprogramming, elevated HIF-1α levels have been reported in various malignancies; however, its serum concentration in malignant salivary gland neoplasms remains unexplored. This study aimed to assess serum HIF-1α levels in patients with salivary gland malignancies. Methods: Serum samples were collected from 30 patients diagnosed with malignant salivary gland neoplasms. HIF-1α concentration was determined using an enzyme-linked immunosorbent assay (ELISA). Results: The mean serum HIF-1α concentration was 89.20 ± 44.56 pg/mL. Exploratory analyses demonstrated higher HIF-1α levels in stage III tumors compared with stage II tumors and in high-grade tumors compared with lower-grade lesions. Conclusions: This is the first study to quantify serum HIF-1α levels in patients with malignant salivary gland neoplasms. The findings suggest that while HIF-1α may have potential as a biomarker, its potential as a biomarker of tumor aggressiveness or of malignant salivary gland neoplasms is limited due to high interindividual variability. Further studies with larger cohorts and standardized methodologies are necessary to establish reference values and clarify the clinical significance of HIF-1α in salivary gland malignancies.