Macrophages, an important component of the innate immune response, are a key regulator of intestinal microenvironment homeostasis. These cells essentially contribute to chronic inflammatory diseases due to their strong plasticity. As is known, ulcerative colitis (UC), a chronic inflammatory disease, is closely related to immune dysfunction. A growing body of evidence suggests that the macrophage is a promising drug target for modulating the intestinal immune systems and regulating the inflammatory microenvironment, thus alleviating the inflammatory responses in UC. The macrophage-based therapy strategies for UC are still at an emerging stage. The advanced drug delivery systems can improve the macrophage-based therapy. This article will review the molecular mechanisms related to macrophage polarization and the interactions between signaling pathways that regulate the pathogenesis of UC and summarize the macrophage-based nanotherapeutic strategies in UC.