The innate immune landscape of the central nervous system (CNS), including the brain and the retina, consists of different myeloid cell populations with distinct tasks to fulfill. Whereas the CNS borders harbor extraparenchymal CNS-associated macrophages whose main duty is to build up a defense against invading pathogens and other damaging factors from the periphery, the resident immune cells of the CNS parenchyma and the retina, microglia, are highly dynamic cells with a plethora of functions during homeostasis and disease. Therefore, microglia are constantly sensing their environment and closely interacting with surrounding cells, which is in part mediated by soluble factors. One of these factors is Osteopontin (OPN), a multifunctional protein that is produced by different cell types in the CNS, including microglia, and is upregulated in neurodegenerative and neuroinflammatory conditions. In this review, we discuss the current literature about the interaction between microglia and OPN in homeostasis and several disease entities, including multiple sclerosis (MS), Alzheimer's and cerebrovascular diseases (AD, CVD), amyotrophic lateral sclerosis (ALS), age-related macular degeneration (AMD) and diabetic retinopathy (DR), in the context of the molecular pathways involved in OPN signaling shaping the function of microglia. As nearly all CNS diseases are characterized by pathological alterations in microglial cells, accompanied by the disturbance of the homeostatic microglia phenotype, the emergence of disease-associated microglia (DAM) states and their interplay with factors shaping the DAM-signature, such as OPN, is of great interest for therapeutical interventions in the future.