Ischemic stroke is a significant health problem affecting over 6 million people in the United States alone. In addition to surgical and thrombolytic therapeutic strategies for stroke, neuroprotective therapies may offer additional benefit. N-acylethanolamines (NAEs) are signaling lipids whose synthesis is upregulated in response to ischemia, suggesting that they may be neuroprotective. To date only three NAEs, arachidonylethanolamide (NAE 204), palmitoylethanolamide (NAE 160) and oleoylethanolamide (NAE 181) have shown to exert neuroprotective effect in animal models for stroke. Here, we describe neuroprotective effects of the hitherto uncharacterized NAEs, lauroylethanolamide (NAE 120) and linoleoylethanolamide (NAE 182) in a middle cerebral artery occlusion model of stroke. Pretreatment with NAE 182 prior to ischemia/reperfusion (I/R) injury resulted in both significantly reduced cortical infarct volume and improved functional outcome as determined using the neurological deficit score. NAE 120 improved neurological deficits without a significant reduction lesion size. Our results suggest that NAEs, as a whole, provide neuroprotection during I/R injury and may have therapeutic benefit when used as complementary treatment with other therapies to improve stroke outcome.