Immune responses contribute to tissue injury and repair during and after ischemic stroke. However, the spatiotemporal and initiating molecular events remain incompletely understood. Here, we show that mice deficient in the phosphatidylserine receptor CD300a, which is highly expressed on brain myeloid cells including Ly6Chi monocytes, exhibited ameliorated neurological deficit after middle cerebral artery occlusion (MCAO). CD300a inhibited signaling through the CD300b-DNAX-activation protein 12 (DAP12) signaling pathway to prevent efferocytosis of apoptotic cells. Deficiency of CD300a enhanced efferocytosis by myeloid cells infiltrating the brain as early as 1 hour after MCAO and reduced release of damage-associated molecular patterns from dead cells, resulting in milder inflammation in the penumbral region. Treatment with an anti-CD300a neutralizing antibody ameliorated the neurological deficit after MCAO. These findings reveal an important role of efferocytosis in the super-acute phase of ischemic stroke pathology and identified CD300a as a target for immunotherapy in treating ischemic stroke.