Organs and tissues contain a large number of tissue-resident macrophages (MΦ-Ts), which are essential for regulating homeostasis and ensuring a rapid response to injury. However, the environmental signals shaping MΦ-Ts phenotypes and the contribution of MΦ-Ts to pathological processes are just starting to be identified. MΦ-Ts isolated from aged animals or patients show alterations in morphology and distribution, defects in phagocytosis and autophagy, and loss of tissue-repair capacity. These variations are closely associated with age-associated disorders, such as inflammaging, which is characterized by cell senescence and a senescence-associated secretory phenotype (SASP) and is frequently observed in patients afflicted with chronic diseases. It seems that the role of these resident populations cannot be avoided in the treatment of aging-related diseases. This review will describe the mechanism by which MΦ-Ts support immune homeostasis and will then discuss how MΦ-Ts facilitate inflammaging and age-related diseases, which will be helpful in the development of new interventions and treatments for chronic diseases of the elderly.