Background: Aplastic anemia (AA), an unusual hematological disease, is characterized by hypoplasia of the bone marrow and failure to form blood cells of all three lineages resulting in pancytopenia. This study aimed to investigate TNF-α-308 and IFN-γ-874 gene polymorphisms and their respective plasma protein levels in patients with AA and healthy controls. Methods: Two hundred and forty individuals were included in this study; the case group comprised 120 AA patients, while 120 healthy individuals served as controls. Genotyping was performed using the PCR-restriction length fragment polymorphism method and TNF-α-308 and IFN-γ-874 plasma levels were evaluated using an ELISA kit. Results: There was a significantly higher prevalence of the IFN-γ-874 genotype in patients with AA than in healthy controls, while the TNF-α-308 genotype was associated with lower risk of developing AA. Furthermore, the levels of both TNF-α-308 and IFN-γ-874 were higher in the plasma of AA patients. Conclusion Our findings suggest that the IFN-γ-874 genotype may be a greater risk factor in the causation of AA, whereas the TNF-α-308 genotype has a protective role in the North Indian population.