Monocytes, including monocyte-derived macrophages and resident microglia, mediate many phases of optic nerve injury pathogenesis. Resident microglia respond first, followed by infiltrating macrophages which regulate neuronal inflammation, cell proliferation and differentiation, scar formation and tissue remodeling following optic nerve injury. However, microglia and macrophages have distinct functions which can be either beneficial or detrimental to the optic nerve depending on the spatial context and temporal sequence of their activity. These divergent effects are attributed to pro- and anti-inflammatory cytokines expressed by monocytes, crosstalk between monocyte and glial cells and even microglia-macrophage communication. In this review, we describe the dynamics and functions of microglia and macrophages in neuronal inflammation and regeneration following optic nerve injury, and their possible role as therapeutic targets for axonal regeneration.