Methylene blue (MB), an FDA-grandfathered drug, has been shown to reduce MRI-defined infarct volume in acute ischemic stroke. However, the efficacy of chronic MB treatment in stroke remains unknown. The goal of this study was to investigate the efficacy of chronic oral MB administration in ischemic stroke using MRI and behavioral tests. We found chronic MB treatment reduced MRI-defined total lesion volumes and improved functional behavioral outcomes, as well as reduced sub-acute hyperperfusion and white-matter damage. Our findings, for the first time, suggest that long-term MB oral administration is safe and has positive therapeutic effects in chronic stroke.