Although infiltration of peripheral monocytes/macrophages is implicated in stroke pathology, in vivo data regarding the deployment of monocytes and their mobilization to the infarct area is scarce. Recent literature showed that mouse monocytes exhibit two distinct populations that represent pro-inflammatory (Ly-6Chi/CCR2+) and anti-inflammatory (Ly-6Clow/CCR2-) subsets and that spleen is a major source for monocyte deployment upon injury. By reducing post-ischemic infection with antibacterial moxifloxacin (MFX) treatment, the present study investigates the effect of the treatment on Ly-6C and CCR2 expression in the spleen following ischemia and the extent to which the effect is associated with attenuation of post-ischemic inflammation and injury. Mice subjected to a middle cerebral artery occlusion (MCAO) showed a significant reduction in their spleen weights compared to sham animals. Compared to vehicle controls, splenocytes obtained from daily MFX-treated mice 7 days after ischemia exhibited significantly reduced mean Ly-6C expression within pro-inflammatory subsets, whereas the distribution of pro- and anti-inflammatory subsets was not different between the treatment groups. Additionally, MFX treatment significantly reduced CCR2 expression in the spleen tissue and in the post-ischemic brain and attenuated infarct size. The study suggests a potential contributing role of spleen monocytes in post-ischemic inflammation and injury. The influence of peripheral inflammatory status on the primary injury in the CNS further implies that the attenuation of post-stroke infection may be beneficial in mitigating stroke-induced brain injury.