Acute myocardial infarction (AMI) and acute ischemic stroke (AIS) continue to be substantial burdens on global health, despite recent advances in care. Current treatment strategies focus on blockage removal and establishment of reperfusion, but there are no approved treatments to protect cells from apoptosis resulting from hypoxia or reperfusion injury. Insulin-like growth factor-1 (IGF-1) is a pleiotropic modulator of mitogenic and anti-apoptotic pathways across multiple cell types. Administration of IGF-1 reduces cell death and promotes recovery following ischemic injury. However, the development of IGF-1 therapeutics for apoptotic injuries has been limited by its short half-life, extensive protein binding, and non-specificity. We aimed to develop a targeted IGF-1 therapeutic, capable of preferential accumulation in injured tissues with large populations of apoptotic cells. A fusion protein consisting of an IGF-1 signaling domain, an albumin backbone, and an Annexin-V targeting domain was optimized for binding to apoptotic cells through iterative protein engineering. In vivo targeting to injured tissue, and in vitro prevention of apoptosis in cardiomyocytes, neurons, and neuroglia was demonstrated for the lead molecule scp776. Single dose scp776 treatment reduced infarct sizes in rat and pig AMI models. In a cynomolgus monkey model of AIS, a 5-day regimen of scp776 reduced lesion volume and neurological deficits within the acute post-ischemic window (first 3 days) and significantly improved survival at two weeks. These results demonstrate the potential of this novel class of targeted growth factors in different tissue types and motivate the clinical assessment of scp776-mediated rescue from acute ischemic injury.