Significance Infection/inflammation is a major contributor to male infertility, and macrophages are likely to be key players in both pathological progression and resolution of the inflammation. We report that macrophage populations in the epididymis and testis are derived from fetal and neonatal monocytes, which are self-maintaining during adulthood. Furthermore, during inflammation, circulating monocytes recruited to the epididymis and testis give rise to inflammatory macrophages that promote tissue damage. These data are significant for our understanding of the origins and maintenance of macrophage subpopulations in both organs; our results point to a fundamental mechanism underpinning male infertility by infection and inflammation, and pave the way for the development of innovative therapeutics to treat this important and common condition.