Helminth parasites have evolved strategies to modulate the host immune response, in order to prevent their own expulsion, while minimising immune-mediated tissue damage associated with infection. Helminths achieve this by inducing an anti-inflammatory/regulatory immune environment in the host, while simultaneously suppressing pro-inflammatory immune responses. Understanding the mechanisms that allow helminth parasites to control the immune environment could lead to new developments in the treatment of autoimmune and inflammatory disorders. Here, we demonstrate that treatment of nonobese diabetic (NOD) mice at 4 weeks of age with the excreted products of Fasciola hepatica (FhES) prevents diabetes in 86% of animals, in stark contrast to the 16% of mice which do not develop disease in the control cohort. Protection afforded by FhES is associated with the production of a regulatory isotype of autoantibody (IgG1) against the dominant autoantigens insulin and gluteraldehyde decarboxylase (GAD), and a suppression in the secretion of IFN-y by insulin-reactive Th1 cells. Following treatment with FhES, a population of anti-inflammatory, IL-10 secreting M2-macrophages was detected in the peritoneum. Interestingly, this population of cells was also found in the pancreatic lymph nodes (PLNs) and pancreas following treatment with FhES. In vitro analysis demonstrated the ability of FhES-induced macrophages to drive the differentiation of regulatory T cells (Tregs) from naïve cells. FhES-induced macrophages likely migrate from the peritoneal cavity to the pancreas and PLNs, where they induce a regulatory immune environment via their modulation of the cytokine milieu and the induction of tolerogenic Tregs, thereby preventing the autoimmune destruction of beta cells and consequent diabetes. Therefore, molecules within FhES represent novel immune-therapeutic agents which hold great potential in the treatment of autoimmune/inflammatory disorders.