Abstract: Ginsenoside Rg1 is a common component of a variety of stroke and diabetes medications, but its anti-stroke effect in diabetic patients is unclear. The aim of this research is to test the therapeutic effect of Rg1 on ischemic stroke in diabetic rats, and elucidate the effect of Rg1 on post-stroke neuro-inflammation. Rg1 significantly reduced the infarct area percent, increased the behavioral score, and reduced the brain water content in diabetic rats after stroke in the diabetic rats. Rg1 reduced the post-stroke inflammatory response and decreased the expression of high mobility group box1 (HMGB1) protein significantly. Elevated level of HMGB1 activity by supplementing exogenous HMGB1 protein abolished the anti-stroke effect of Rg1, which suggests that HMGB1 is involved into the anti-stroke effect of Rg1 in the diabetic rats.