<p>Monomeric C-reactive protein (mCRP) is a key acute phase reactant involved in inflammatory responses. Cerebral ischemia triggers persistent neuroinflammation. However, the effects of mCRP on global cerebral ischemia are poorly understood. In present study, mCRP was intracerebroventricularly injected to brain, and a bilateral common carotid artery ligation (BCAL) model was established in CX3CR1^GFP/+ mice. Behavioral tests were employed to evaluate spontaneous activity, rotarod performance (latency to fall),&#xa0;and forelimb grasping strength in mice. Nissl and Fluoro-Jade C (FJ-C) staining were used to assess neuronal injury. Skeletonization analysis and CD16/32, CD206 staining were used to assess microglial activation. RT-qPCR was applied to evaluate the changes of inflammatory factors and complement system. Primary cultured microglia and oxygen–glucose deprivation (OGD) model were used to verify the effects of mCRP on microglia <i>in vitro</i>. Results showed that mCRP treatment exacerbated behavioral performance post-ischemia. Nissl staining showed that mCRP caused a significant decrease in neuronal density. Additionally, FJ-C staining indicated an increase in degenerative cells after mCRP treatment. Immunofluorescence analysis revealed an increase in CD16/32 and CD206-positive microglia, and skeletonization analysis showed increased de-ramification of microglia following mCRP administration. RT-qPCR results further demonstrated that mCRP treatment upregulated the expression of pro-inflammatory and anti-inflammatory factors, as well as complement system components, in both brain tissue and primary cultured microglia following ischemia or OGD. These findings suggest that mCRP significantly enhances microglial activation, increases the level of inflammatory response, exacerbates neuronal loss and degenerative damage, and impairs behavioral performance after ischemia.</p>