Helminths have strong immunoregulatory properties that may be exploited in treatment of chronic immune disorders, such as multiple sclerosis and inflammatory bowel disease. Essential players in the pathogenesis of these diseases are proinflammatory macrophages. We present evidence that helminths modulate the function and phenotype of these innate immune cells. We found that soluble products derived from the Trichuris suis (TsSP) significantly affect the differentiation of monocytes into macrophages and their subsequent polarization. TsSPs reduce the expression and production of inflammatory cytokines, including IL‐6 and TNF, in human proinflammatory M1 macrophages. TsSPs induce a concomitant anti‐inflammatory M2 signature, with increased IL‐10 production. Furthermore, they suppress CHIT activity and enhance secretion of matrix metalloproteinase 9. Short‐term triggering of monocytes with TsSPs early during monocyte‐to‐macrophage differentiation imprinted these phenotypic alterations, suggesting long‐lasting epigenetic changes. The TsSP‐induced effects in M1 macrophages were completely reversed by inhibiting histone deacetylases, which corresponded with decreased histone acetylation at the TNF and IL6 promoters. These results demonstrate that TsSPs have a potent and sustained immunomodulatory effect on human macrophage differentiation and polarization through epigenetic remodeling and provide new insights into the mechanisms by which helminths modulate human immune responses.—Hoeksema, M. A., Laan, L. C., Postma, J. J., Cummings, R. D., de Winther, M. P. J., Dijkstra, C. D., van Die, I., Kooij, G. Treatment with Trichuris suis soluble products during monocyte‐to‐macrophage differentiation reduces inflammatory responses through epigenetic remodeling.