Silent information regulator 1 (SIRT1), a conserved lysine deacetylase, is an important contributor to the function of macrophages, which are the scavengers of the innate immune system. Macrophages are part of the first line of defense against infection and key players in immunity due to their ability to survey tissue for infections or damage, release inflammatory cytokines, and clear pathogens. Macrophage function deteriorates with age and is a common indicator of immunosenescence. SIRT1 is known to influence multiple aspects of macrophage physiology, particularly proliferation, self-renewal, migration, the regulation of macrophage polarization, and the ability of macrophages to clear pathogens via phagocytosis and inflammasome signaling. Furthermore, mammalian SIRT1 and orthologous Sir2 in other organisms have well-defined roles in aging. Therefore, in this chapter, we discuss evidence that links SIRT1 to macrophage behavior and function, explore its role in inflammatory pathways linked to aging, and highlight key research questions in immunosenescence and the implications for epigenetic and non-epigenetic roles of SIRT1.