Astrocytes support normal brain function, but may also contribute to neurodegeneration when they be-come reactive under pathological conditions such as stroke. However, the molecular underpinnings of this con-text-dependent interplay between beneficial and detrimental properties in reactive astrogliosis have remained in-completely understood. Therefore, using the RiboTag technique, we immunopurified translating mRNAs specifi-cally from astrocytes 72 hr after transient middle cerebral artery occlusion in mice (tMCAO), thereby generating a stroke-specific astroglial translatome database. We found that compared to control brains, reactive astrocytes af-ter tMCAO show an enrichment of transcripts linked to the A2 phenotype, which has been associated with neuro-protection. However, we found that astrocytes also upregulate a large number of potentially neurotoxic genes. In total, we identified the differential expression of 1,003 genes and 38 transcription factors, of which Stat3, Sp1, and Spi1 were the most prominent. To further explore the effects of Stat3-mediated pathways on stroke pathogen-esis, we subjected mice with an astrocyte-specific conditional deletion of Stat3 to tMCAO, and found that these mice have reduced stroke volume and improved motor outcome 72 hr after focal ischemia. Taken together, our study extends the emerging database of novel astrocyte-specific targets for stroke therapy, and supports the role of astrocytes as critical safeguards of brain function in health and disease.