Macrophages are double-edged swords in the post-stroke environment, contributing to both neuroregeneration and neurodegeneration, yet the molecular switches driving their neurotoxic transition remain elusive. We previously showed that the neurotoxic potential of macrophages toward cultured cortical neurons is markedly attenuated when they are co-cultured with dorsal root ganglia neurons. RNA sequencing revealed that this neuroprotective shift is accompanied by robust upregulation of cell cycle–related pathways in macrophages, and bioinformatic analysis identified Aurora kinase (AURK) as a central regulatory hub. Functional studies underscored the importance of AURK, as pharmacological and RNAi-mediated inhibition reversed the attenuation of macrophage neurotoxicity by the co-culture paradigm. In in vivo analyses, temporal profiling of FACS-sorted brain macrophages showed that AURK expression is markedly suppressed by 7 days post-stroke, coinciding with peak induction of the senescence marker p21. Consistent with these findings, integrative single-cell RNA sequencing from publicly available datasets on stroke mouse models also showed that proliferating macrophage subclusters exhibit higher expression of AURKs alongside decreased p21 levels. In a mouse photothrombotic stroke model, splenectomy conducted 2 weeks prior to stroke induction led to a reduction of infarct volume, whereas intravenous splenocyte reconstitution exacerbated infarction, confirming the neurotoxic role of infiltrating macrophages. This exacerbation was markedly blunted when transplanted splenocytes were engineered to overexpress AURK, indicating that AURK activation enables macrophage reprogramming and limits inflammation-related brain damage. Building upon these mechanistic insights, we further investigated whether Macrophage Colony-Stimulating Factor (M-CSF) could be utilized to upregulate AURK expression in macrophages. M-CSF–treated macrophages showed a substantial reduction in neurotoxicity toward cortical neurons in vitro. Together, these findings identify AURK as a key modulator of macrophage-mediated neurotoxicity and demonstrate that targeting AURK signaling via molecular approaches or M-CSF intervention offers a promising therapeutic strategy to limit post-stroke secondary neurodegeneration.