Objective: COVID-19 is a serious respiratory and vascular disease that impairs the protective function of the endothelial barrier. Endothelial nitric oxide synthase (eNOS), the most important isoform for nitric oxide (NO) production, is mostly expressed in endothelial cells. Therefore, this study aims to evaluate whether eNOS G894T and variable tandem repeat number (VNTR) functional variants show predisposition to developing COVID-19. Materials and Methods: The study includes a total of 384 subjects (284 COVID-19 patients and 100 healthy controls). Two eNOS gene variants (G894T and VNTR) were genotyped using the polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods, with the results being evaluated using statistical methods. Results: A significant association has been identified between eNOS G894T and COVID-19. For the eNOS G894T variant, the T/T genotype (p=0.035) and T allele carriers (p=0.030) appear to have an increased risk of developing COVID-19. The eNOS G894T G/G genotype (p=0.030) was more common in the control group compared to the patient group. No significant difference was found between groups regarding the eNOS VNTR genotype and allele frequencies (p>0.05). The genotypes of the patient and control groups for these variants were in Hardy-Weinburg equilibrium (HWE). Conclusion: These results provide evidence supporting the hypothesis that the eNOS G894T variant is associated with an increased risk of developing COVID-19 in the Turkish population. These findings may lead to the emergence of new treatment options. Further research is required to understand the molecular mechanisms involved in the pathogenesis of the disease.