Background <p>Ischemic stroke is a detrimental disease that could can lead to disability and death., Multiple pathophysiological processes are involved in ischemic stroke, from the initial stages to the chronic stages. Oxylipins are a class of bioactive lipid metabolites mainly derived from the oxidation of omega-3 and omega-6 polyunsaturated fatty acids (PUFAs). Emerging evidence based on laboratory results shows that diverse subclasses of oxylipins exert protective or harmful effects in ischemic stroke, and an increasing number of clinical studies have reported an association between oxylipins and ischemic stroke. Oxylipins have been widely reported in cardiovascular disease, however, there are no reviews on the implications of oxylipin regulation in ischemic stroke.</p> Aim of review <p>In this review, in addition to discussing the biosynthesis and response signaling of oxylipins in many diseases, we aim to provide an overview of how oxylipin modulates the pathophysiology of ischemic stroke and influences the relevant clinical phenotypes and promising therapeutics to regulate oxylipins.</p> Key scientific concepts of the review <p>Oxylipins hold extensive research potential in lipidomics. This review systematically elucidates the pivotal roles of distinct oxylipins subclasses in ischemic stroke pathogenesis, encompassing pathophysiological mechanisms such as inflammatory responses, oxidative stress, immune response, thrombosis, cellular apoptosis, and vascular homeostasis dysregulation. The associations between oxylipins and ischemic stroke phenotypes are obvious. However, more metabolomic studies are needed to identify oxylipin biomarkers in patients with ischemic stroke across different samples or cell types to bridge oxylipins regulation with clinical phenotype intervention.</p>