Intracerebral hemorrhage (ICH) is a devastating subtype of stroke with high mortality and limited therapeutic options. Microglia and macrophages are myeloid cells that are rapidly recruited into ICH lesions where they contribute to secondary brain injury. However, the driver of myeloid cell neurotoxicity remains incompletely understood. Here, we interrogated extracellular matrix metalloproteinase inducer (EMMPRIN, CD147) in promoting microglia/macrophage neurotoxicity in ICH. Using both AAV-mediated knockdown and CX3CR1Cre:EMMPRINfl/fl mice, we demonstrate that EMMPRIN deletion in microglia/macrophages reduced neuronal death and improved functional recovery after ICH. EMMPRIN-mediated neurotoxicity in ICH was associated with elevation of matrix metalloproteinases, and reduced signaling through the p38/MAPK, MEF2C transcription factor and Bcl2 anti-apoptotic pathway. Correspondent with lower injury, EMMPRIN deletion enhanced neurogenesis and oligodendrogenesis in ICH. These findings establish EMMPRIN elevation in myeloid cells as a prominent regulator of ICH pathophysiology and a promising therapeutic target to limit secondary injury and promote brain repair.