Abstract: Parasitic helminths, taxonomically comprising trematodes, cestodes, and nematodes, are multicellular invertebrates widely disseminated in nature and have afflicted humans continuously for a long time. Helminths play potent roles in the host by generating a variety of novel molecules, including some excretory/secretory products and others that are involved in intracellular material exchange and information transfer as well as the initiation or stimulation of immune and metabolic activation. The helminth-derived molecules have developed powerful and diverse immunosuppressive effects to achieve immune evasion for parasite survival and establish chronic infections. However, they also improve autoimmune and allergic inflammatory responses and promote metabolic homeostasis by promoting metabolic reprogramming of various immune functions, and then inducing alternatively activated macrophages, T helper 2 cells, and regulatory T cell-mediated immune responses. Therefore, a deeper exploration of the immunopathogenic mechanism and immune regulatory mechanisms of helminth-derived molecules exerted in the host is crucial for understanding host-helminth interactions, as well as the development of therapeutic drugs for infectious or non-infectious diseases. In this review, we focus on the properties of helminth-derived molecules to give an overview of the most recent scientific knowledge about their pathogenic and pharmacopeial roles in immune-metabolic homeostasis.