Macrophages, as a crucial component of the body's immune system, play a vital role in the onset, progression, and outcome of diseases. Discoidin domain receptors (DDRs), important members of the novel receptor tyrosine kinase superfamily, exhibit unique functions in macrophage physiology. Through interactions with the extracellular matrix, DDRs activate signaling pathways such as p38 MAPK and NF-κB, regulating macrophage adhesion, migration, and secretory functions, thereby influencing their behavior in diseases. Recent studies have indicated a direct correlation between DDRs and the progression of various diseases, including inflammation, cancer, and fibrosis. However, there remain numerous knowledge gaps regarding the specific mechanisms by which DDRs function in macrophage-mediated diseases. This article provides an in-depth summary of the regulatory mechanisms of DDRs on macrophages, detailing their modulatory roles in various diseases through macrophages and their underlying mechanisms. The aim is to offer new insights into biomedical therapies targeting DDRs and the development of novel drugs.