Inflammation is a significant driver of ischemic stroke pathology in the brain. To identify potential regulators of inflammation, we performed single-cell RNA sequencing (scRNA-seq) of young and aged mouse brains following stroke and found that interferon alpha-inducible protein 27 like 2 A (Ifi27l2a) was significantly up-regulated, particularly in microglia of aged brain. Ifi27l2a is induced by interferons for viral host defense and has been linked with pro-inflammatory cellular mechanisms. However, its potential role in neurodegeneration is unknown. Using a combination of cell culture, experimental stroke models in mice, and human autopsy brain samples, we demonstrated that induction of Ifi27l2a occurs in microglia in response to aging, ischemic stroke, and pro-inflammatory molecules. We further showed that induction of Ifi27l2a in microglia was sufficient to stimulate mitochondrial ROS production and promote a pro-inflammatory phenotype. Lastly, using an ischemic stroke model, we demonstrated that hemizygous deletion of Ifi27l2a (Ifi27l2a