Oral cancer is a common cause of morbidity and mortality with poor prognosis in head and neck carcinomas. The cancer is a complex structure, where 50%–60% of solid tumors exhibit areas of hypoxia which is influenced by the transcriptional activity of hypoxia-inducible factor (HIF). HIF promotes stemness and proliferation of vessel-like structures tumors which are responsible for invasion and metastasis. Aim: To evaluate and correlate the expression of HIF1-α and Nestin in tumor center and periphery of nonmetastatic, and recurrent oral squamous cell carcinoma (OSCC) and its association with vasculogenic mimicry. Materials and Methods: About 60 histopathological proven cases of OSCC with proper tumor center and periphery were collected. Among them 25 are nonmetastatic, 25 metastatic, and 10 recurrent cases of OSCC. Immunohistochemical analysis of HIF, Nestin, and CD31/PAS (periodic acid Schiff) was done. Results: Based on the extent of tumor cells stained, staining intensity and index score, expression of both HIF and Nestin was highly significant in periphery of metastatic OSCC with a P value of 0.003* and 0.001*. The total number of vessels expressed in nonmetastatic, metastatic, and recurrent OSCC was not significant but the overall expression of CD31/PAS was significant in the periphery of the tumor with a P value of 0.024*. Correlating the overall expression, HIF showed a positive relation with Nestin and CD31/PAS with a P value of 0.026* and 0.038* in nonmetastatic OSCC using Pearson’s correlation coefficient analysis. Conclusion: Based on the above results hypoxia plays a vital role in cancer stem cells maintenance with the formation of vessel-like structures by tumor cells at an early stage of cancer development. © 2024 Elsevier B.V., All rights reserved.