Background: Oral cancer is the common reason for the poor prognosis in head and neck carcinomas and the increase in morbidity and mortality rates. The biological behavior of cancer is a complex process. About 50-60% of solid tumors exhibit hypoxic areas within the tumor stroma, which was influenced by the transcriptional activity of hypoxia inducible factor (HIF). HIF promotes stemness and the proliferation of vessel-like structures in tumors, which leads to invasion and metastasis. Aim: To evaluate and correlate the expression of HIF- 1α, MCT1, NESTIN, and SALL2 in the tumor proper and tumor periphery of non- metastatic, metastatic, and recurrent OSCC. Materials and Methods: A Total of 60 proven OSCC cases with proper tumor center and periphery were collected. Among them, 25 were nonmetastatic, 25 were metastatic, and 10 were recurrent cases of OSCC. Immunohistochemical analysis of HIF- 1α, MCT1 NESTIN, SALL2, and CD31/PAS double staining was done. Results: Depending on the extent of stained tumor cells, the intensity of staining, and the index score, the expressions of both MCT1, SALL2, and NESTIN were highly significant in the periphery of OSCC with a Pvalue of 0.001. The total number of vessels expressed in non-metastatic, metastatic, and recurrent OSCC were not significant, but overall expression of CD31/PAS was statistically significant in the periphery of the tumor with P value -0.024. Conclusion: Based on the above results, it is observed that the role of hypoxia helped in cancer stem cell (CSC) maintenance with the formation of vessel-like structures by tumor cells at an early stage of cancer promotes its development and recurrence. © 2025 Elsevier B.V., All rights reserved.