The activation of the NF-kB pathway leading to the production of proinflammatory cytokines is a critical feature in innate antiviral immunity. However, in SARS-CoV-2 infection, a high number of cases with a prolonged late-stage stimulation of cytokine production that leads to a cytokine storm phenotype, an undesirable, dangerous immune-related state that can cause multiple organ failures, have been reported. To treat this, immunosuppressants with selective action on the innate NF-kB pathway are urgently required. Bitter gourd (Momordica charantia L.) has been reported to yield anti-inflammatory activity, thus might be a potential candidate for such effort. In this study, we carried out experimental procedures on the PGRP-LB mutant line of Drosophila melanogaster to examine the immunosuppressive effect of Momordica charantia L. fruit extract (MCFE) on the NF-kB pathway. Initial phytochemical screening revealed that Momordica charantia L. fruit extract contains alkaloids, flavonoids, tannins, and saponins. Furthermore, the phenotypical analysis demonstrated that MCFE could improve the survival and locomotor of the PGRP-LB mutant line of Drosophila melanogaster in a concentration-dependent manner. Additional gene expression analysis revealed that the expression of dpt and dro, two important downstream genes in the Imd (NF-kB) pathway of D. melanogaster, was significantly reduced, in a different expression profile, in response to MCFE treatment. However, it is important to note that while the expression of dpt was dramatically repressed in all extract-treated groups, the expression of dro occurred in a concentration-dependent manner. These results strongly support the notion that Momordica charantia L. can reduce the expression of proinflammatory cytokines downstream of the NF-kB pathway, hence potential to be used as a source candidate to harvest prospective immunosuppressive compounds to alleviate the cytokine storm condition.