Allopathic medicines play a key role in the prevention and treatment of diseases. However, long-term consumption of these medicines may cause serious undesirable effects that harm human health. Plant-based medicines have emerged as alternatives to allopathic medicines because of their rare side effects. They contain several compounds that have the potential to improve health and treat diseases in humans, including their function as immunomodulators to treat immune-related diseases. Thus, the discovery of potent and safe immunomodulators from plants is gaining considerable research interest. Recently, Drosophila has gained prominence as a model organism in evaluating the efficacy of plant and plant-derived substances. Drosophila melanogaster “fruit fly” is a well-known, high-throughput model organism that has been used to study different biological aspects of development and diseases for more than 110 years. Most developmental and cell signaling pathways and 75% of human disease-related genes are conserved between humans and Drosophila. Using Drosophila, one can easily examine the pharmacological effects of plants/plant-derived components by employing a variety of tests in flies, such as survival, anti-inflammatory, antioxidant, and cell death tests. This review focused on D. melanogaster’s potential for identifying immunomodulatory features associated with plants/plant-derived components.