Aim and objective: The current study aimed to propose Aquaporin-1 (AQP1) as an endothelial marker and thus explore its role in oral squamous cell carcinoma. Materials and methods: The study included 30 cases of oral squamous cell carcinoma (OSCC) and 10 normal controls. All the sections were subjected to immunohistochemistry using AQP1 antibody. Images were captured, and quantification of blood vessels was done by assessing the mean microvascular density (MVD) using an image analyzer, and statistical data were computed using one-way analysis of variance test. Results: The results demonstrated a significant expression of AQP1 in blood vessels of tumor and showed a significant statistical correlation (p value < 0.05) between mean vascular densities of controls and OSCC cases. Conclusion: The results have demonstrated a strong immunolocalization of AQP1 in the tumor vasculature, thereby proposing it as a selective marker for the endothelium and suggests its possible involvement in tumor angiogenesis, growth, progression, and prognosis. Clinical significance: Angiogenesis is a crucial phenomenon in tumor progression. Aquaporin-1 is a proven marker for the endothelial vasculature, and being a functionally efficient protein associated with the progression of tumor through tumor angiogenesis, its blockade can serve in the downregulation of tumor progression.