The invasion of activated fibroblasts is a key mechanism of tissue fibrosis pathology. The recognition and uptake of apoptotic cells can induce the anti-fibrogenic programming of macrophages. We demonstrate that after interacting with apoptotic cells, macrophages secrete bioactive molecules that antagonize TGF-β1-induced increases in myofibroblast (fibroproliferative) phenotypic markers and reduce the enhanced invasive capacity of TGF-β1- or EGF-treated mouse lung fibroblasts (MLg). Furthermore, numerous treatment strategies prevented the anti-fibrotic effects of conditioned media, including transfection of macrophages with COX-2 or RhoA siRNAs or treatment of MLg cells with receptor antagonists for prostaglandin E2 (PGE2), PGD2, or hepatocyte growth factor (HGF). Additionally, administration of apoptotic cells in vivo inhibited the bleomycin-mediated invasive capacity of primary fibroblasts, as well as adhesion and extracellular matrix protein mRNA expression. These data suggest that the anti-fibrogenic programming of macrophages by apoptotic cells can be used as a novel tool to control the progressive fibrotic reaction.