Background <p>Gastrointestinal tract (GIT) cancers are the most lethal cancers with a high incidence and poor prognosis. Vascular endothelial growth factor (VEGF) glycoprotein plays an essential role in tumour neovascularization, especially in cancers of the gastrointestinal tract. There are numerous functional polymorphisms reported in the <i>VEGF</i> which lead to either upregulation or downregulation of VEGF expression.</p> Objective <p>The present review focuses on the role of <i>VEGF</i> functional polymorphisms in influencing the risk and prognosis of various GIT cancers.</p> Method of study <p>This systematic review was done by Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, and Participant, Intervention, Comparison, Outcomes and Studies (PICOS) criteria were followed for designing the study. A total of 183 articles were retrieved from Google Scholar, PubMed and ScienceDirect using various keywords. After full-text evaluation and applying the literature selection criteria, 108 articles were selected in the review. The role of <i>VEGF</i> promoter polymorphisms in influencing various transcription factor binding sites (TFBS) in the <i>VEGF</i> promoter was studied by performing an in silico analysis.</p> Results <p>This review article summarized the findings of the studies on the associations of <i>VEGF</i> promoter polymorphisms with various GIT cancers. The effect of the <i>VEGF</i> promoter polymorphisms on cancer risk and prognosis varied between different ethnicities and different GIT cancers. The in silico analysis revealed that the <i>VEGF</i> polymorphisms alter the TFBS, leading to attenuation of the functional activity of the transcription factors which might have importance in the GIT cancer development.</p> Conclusion <p>VEGF is as an important biomarker for studying the disease susceptibility, progression and prognosis in GIT cancers.</p>