Low frequency whole body vibration (WBV; 40 Hz) therapy is a novel treatment that mimics the effects of exercise and may be a useful alternative for individuals that are unable to withstand traditional physical rehabilitation procedures. This may be particularly useful for post-menopausal women following stroke, as females are much more likely than males to have a stroke and a more severe stroke. In a published study using female rats, we demonstrated that post-stroke WBV for one month improves motor function and reduces infarct volume in addition to increasing levels of circulating irisin, a protein hormone secreted from muscles. The aim of the current study is to understand the efficacy of irisin in reducing stroke outcomes in middle-aged rats of both sexes. Rats of both sexes were assigned either tMCAO (90 mins) or sham surgery randomly and subsequent intraperitoneal injection of either recombinant irisin (0.2mg/g body weight) or saline vehicle (0.9%) was given at 4.5 hours. Rats were then treated with irisin or saline once a week for 30 days. On day 23 after tMCAO, rats were subjected to neurobehavioral and spatial learning testing to evaluate postural reflex, sensorimotor integration, proprioception, hippocampus-dependent learning and spatial memory. Following behavioral testing, rat brains were collected for histopathological analysis. Post-tMCAO irisin treatment reduced infarct volume, lessened cognitive deficits, and improved behavioral performance compared to saline treated rats.