Immunomodulation is a diverse process by which immunomodulators enhance or suppress immune responses to control disease progression. Immunomodulators are a broad class of drugs that include immunosuppressants and immunostimulants. These agents have been used to fight against the dysregulated immune responses observed during tissue/organ transplantation and disorders, such as rheumatoid arthritis, ulcerative colitis, and cancers. Immunomodulators obtained from a myriad of plant sources are a major class of compounds that are known to have medicinal properties and are used for the treatment of various diseases. However, the mechanisms underlying the action of plant-derived compounds are poorly understood. Here, we discuss the major classes of plantbased immunomodulators with examples and their effects on the major signaling pathways, such as the nuclear factor kappa light chain enhancer of activated B cells (NF-κB), mitogen-activated protein kinase (MAPK), and mammalian target of rapamycin pathways. Importantly, we discuss the preclinical and clinical research to date to understand the importance of these immunomodulators. Overall, this review highlights the significance of plantbased immunomodulators as an alternative therapeutic strategy for combating various diseases.