Objective To investigate the expression of small ubiquitin-like modifier proteins specific protease 3 (SENP3) in microglia of mice with ischemic stroke and its relationship with the progression of ischemic stroke. Methods The experimental animals were divided into control group, ischemic stroke day 1 group and ischemic stroke day 7 group (3 mice per group). The expression of inducible nitric oxide synthase (iNOS), argniase-1 (ARG-1), SENP3 and c-Jun N-terminal kinase (JNK) phosphorylation levels in the striatum were detected by immunoblotting. The expression of iNOS and ARG-1 in mouse striatum microglia was detected by immunofluorescence double labeling. Results Compared with the control group, the expression of SENP3 and the phosphorylation level of JNK in the ischemic stroke group increased significantly, and the expression of the marker iNOS of Ml type microglia increased significantly. The expression of the marker ARG-1 of M2 type microglia increased significantly in the day 7 group of ischemic stroke. The immunofluorescence double-labeled result of striatum ionized calcium binding adapter molecule 1 (Ibal) and iNOS, Ibal and ARG-1 were consistent with the result of immunoblotting. Conclusion In the early stage of ischemic stroke, the expression of SENP3 in microglia increases, which promote the cerebral inflammatory response by affecting the level of JNK phosphorylation and the polarization of microglia, and participate in the progression of ischemic stroke.