Background: The spleen, a substantial reservoir of non-differentiated monocytes, may play a crucial role in the pathophysiology of post-ischemic inflammation and influence outcomes after ischemic stroke. ----- Aim of the study: To analyze splenectomy as a preclinical intervention in murine models of ischemic stroke. ----- Methods: Following systematic searches of PubMed, Scopus and Web of Science, a qualitative synthesis of study characteristics was performed, and the effect of splenectomy estimated by a three-level random-effects meta-analysis of infarct volumes and a conventional two-level random-effects meta-analysis of neurological deficit scores. ----- Results: Database searches identified a total of 14 studies, 13 of which were used for meta-analysis. The ischemic lesion volumes were reduced in splenectomized animals compared to the control groups (difference in standardized mean differences: - 1.42; 95% CI [- 1.98, - 0.85]; 95% PI [- 2.03, - 0.80]; I2(2) = 19.04%; 95% CI [0.00%, 65.49%]; I2(3) = 47.24%; 95% CI [0.00%, 85.23%]) and neurological deficit scores were improved (- 1.20; 95% CI [- 2.20, - 0.20]; 95% PI [- 4.58, 2.18]; I2 = 77.5%; 95% CI [50.0%, 89.9%]). A subgroup analysis for infarct volumes showed that splenectomy performed prior to ischemia achieved a higher reduction of the ischemic lesion than when splenectomy was performed immediately prior or after stroke. Although the overall effect size of splenectomy could be classified as large, there was a significant presence of risks of bias, study heterogeneity, and a potential presence of publication bias. ----- Conclusion: Despite limitations related to heterogeneity, risks of bias, and potential publication bias, this meta-analysis points to the spleen and its functional cell populations as promising targets for the therapeutic modulation of post-stroke inflammation.