Approved treatments for acute ischemic stroke (AIS) include thrombolysis (clot dissolution) and thrombectomy (clot removal). Most patients are ineligible for these procedures because they must be initiated within 4.5h (thrombolysis) or 24h (thrombectomy) of AIS symptom onset. New targets for intervention are needed. Here we evaluate the contribution from endothelial cell (EC) autophagy to outcomes of AIS. AIS creates a nutrient stress and activates EC autophagy. Heightened EC autophagy in response to AIS helps to : (i) identify, tether, and shuttle damaged proteins to the lysosome for degradation and recycling; (ii) generate ATP from recycled macromolecules; and (iii) preserve arterial function by enabling EC nitric oxide production. First we hypothesized that depleting EC autophagy worsens outcomes of AIS. Adult mice with intact autophagy (ATG3 WT ) or depletion of autophagy regulated gene 3 (Atg3) specifically in ECs (ATG3 EC-/- ) were challenged with 60-min middle cerebral artery occlusion followed by 23 h reperfusion. By design, AIS increased (p<0.05) EC autophagy in brains from ATG3 WT but not ATG3 EC-/- mice. Infarct volume was larger, and neurobehavioral and physical deficits were more severe (all p<0.05), in ATG3 EC-/- vs. ATG3 WT mice (n=7 per group). Second, we hypothesized that amplifying autophagy improves outcomes of AIS. For 3-weeks adult mice consumed standard chow that was (rapa) or was not (control) supplemented with the mammalian target of rapamycin complex 1 (mTORC1) inhibitor rapamycin, a potent activator of autophagy. As evidence of mTORC1 inhibition, fasting-induced p-s6K : s6 was greater (p<0.05) in liver segments from rapa vs. control mice (n=4 per group). AIS-induced outcomes concerning infarct volume, and neurobehavioral and physical performance, were superior in rapa vs. control mice (n=8 per group). These results indicate EC autophagy depletion worsens, whereas EC autophagy activation mitigates, outcomes of AIS. Our ongoing studies are targeting EC metabolism to improve outcomes of AIS.