As of 2015, stroke is the fifth leading cause of death in US and remains to be a major cause of long-term disability with limited treatment options. Angiotensin II (Ang II) is a peptide hormone that mediates its actions through two major types of receptors, angiotensin type 1 (AT1R) and type 2 (AT2R) receptors. While, AT1R causes vasoconstriction, inflammation and ischemic damage after stroke, AT2R is considered beneficial. Experimentally, angiotensin II type 1 receptor blockers (ARBs) have consistently improved stroke outcome yet clinical data showed controversial results with a trend towards worsened stroke outcome due to BP lowering. AT2R stimulation has emerged as a new tactic to reap the beneficial actions of AT1R blockade without affecting the blood pressure. Our work aimed to examine the beneficial effects of acute AT2R stimulation after stroke using the novel, non-peptide and orally available AT2R agonist, compound 21 (C21). We showed for the first time neurovascular protection and sustained functional improvement up to 7 days with a single C21 treatment after stroke. Furthermore, we have shown a sustained proangiogenic response with C21 treatment that was mediated through endothelial upregulation of brain derived neurotrophic factor (BNDF). Our findings include characterization of IL-10 expression after ischemic stroke and highlighting its involvement in C21 mediated neuroprotection in vivo. Yet, C21 was still able to provide direct neuroprotection in primary neuron cultures. Lastly, we assessed the AT2R expression in type 2 diabetic GK rats and found lower expression levels after stroke compared to Wistars which lead to impaired efficacy to AT1R blockade after stroke. Our work provides better understanding of the mechanisms of the beneficial actions of AT2R stimulation after stroke and paves the way for translating C21 and future non-peptide AT2R agonists to the clinical setting as acute stroke treatment.