TMT-coupled proteomic analysis was conducted on mouse brain cortex tissue from five time-points up to four weeks post-stroke in the DH-MCAO mouse model. Nearly-half of the detected proteome was altered following stroke, with <10% of changes at relatively large scales. Clustering on the changed proteome defined four distinct expression patterns characterized by temporal and quantitative changes in innate and adaptive immune response pathways, and cytoskeletal and neuronal remodeling. Further analysis on a subset of top-hits, which temporally responded to stroke with relatively large and sustained changes, revealed that they were highly correlated to different cortical cytokines, and thereby potential pharmacodynamic biomarker candidates for inflammation-targeting therapies. Closer examination of the top enriched neurophysiologic pathways identified 57 proteins potentially associated with post-stroke recovery. Altogether, our study generated a rich dataset with candidate proteins worthy of further validation as biomarkers and/or therapeutic targets for stroke.