Background PTGS2 encodes cyclooxygenase‐2 (COX‐2), which catalyses the committed step in prostaglandin synthesis. Various in vivo and in vitro data suggest that COX‐2 mediates the VEGF signalling pathway. In silico analysis performed in TCGA, PanCancer Atlas for head and neck cancers, demonstrated significant expression and co‐expression of PTGS2 and genes that regulate VEGF signalling. This study was designed to elucidate the expression pattern of PTGS2 and genes regulating VEGF signalling in patients with locally advanced oral squamous cell carcinoma (OSCC). Methodology Tumour and normal tissue samples were collected from patients with locally advanced OSCC. RNA was isolated from tissue samples, followed by cDNA synthesis. The cDNA was used for gene expression analysis (RT‐PCR) using target‐specific primers. The results obtained were compared with the in silico gene expression of the target genes in the TCGA datasets. Co‐expression analysis was performed to establish an association between PTGS2 and VEGF signalling genes. Results Tumour and normal tissue samples were collected from 24 OSCC patients. Significant upregulation of PTGS2 expression was observed. Furthermore, VEGFA, KDR, CXCR1 and CXCR2 were significantly upregulated in tumour samples compared with paired normal samples, except for VEGFB, whose expression was not statistically significant. A similar expression pattern was observed in silico, except for CXCR2 which was highly expressed in the normal samples. Co‐expression analysis showed a significant positive correlation between PTGS2 and VEGF signalling genes, except for VEGFB which showed a negative correlation. Conclusion PTGS2 and VEGF signalling genes are upregulated in OSCC, which has a profound impact on clinical outcomes. This study was designed to elucidate the expression pattern of PTGS2 and genes regulating VEGF signalling in patients with locally advanced oral squamous cell carcinoma. Significant upregulation of PTGS2, VEGFA, KDR, CXCR1, and CXCR2 expression were observed in tumour samples compared with paired normal samples. This study underscores the clinical relevance of these genes, pointing to potential links between disease aggressiveness and adverse prognostic factors.