Prostaglandins play a key role in modulating the inflammatory response in the central nervous system. They are synthesized from arachidonic acid via the enzyme cyclooxygenases (COX). The Cox-1 isoform is highly enriched in microglia. In response to infection or tissue damage, microglia become reactive which is associated with phagocytosis and pro-inflammatory function. Concurrently, selective Cox-1 inhibition has been shown to ameliorate pathological effects in several neurodegenerative diseases. So far, it is not known which impact Cox-1 expression has on the regulation of microglia activity. To answer this question, we first established an inducible microglia-selective Cox-1 knockout mouse line. Then, we take advantage of the optic nerve crush (ONC) model, in which an injury at the retinal ganglion cell axon induces their cell death and triggers a well-defined inflammatory response. When we analysed the microglia 7 days after ONC in wildtype animals, we found a robust increase of the CD68 content and a shift to an amoeboid morphology confirming microglia reactivity. Additionally, we found an increase in phagocytic cups in the retinal ganglion cell layer. Remarkably, this phenotype was abolished with Cox-1 knockout. Similarly, we found that in control animals microglia reactivity after ONC propagated throughout the retinal ganglion cell trajectory to retinorecipient areas (dorsal lateral geniculate nucleus, superior colliculus), and a second order processing area the primary visual cortex. Upon Cox-1 loss, also this microglia reactivity is attenuated. In summary, our results demonstrate that Cox-1 plays an important role for modulating microglia reactivity and potentially influencing neuroinflammation.