In critical limb ischemia (CLI), overproduction of reactive oxygen species (ROS) and impairment of neovascularization contribute to muscle damage and limb loss. Cerium oxide nanoparticles (CNP, or ‘nanoceria’) possess oxygen-modulating properties which have shown therapeutic utility in various disease models. Here we show that CNP exhibit pro-angiogenic activity in a mouse hindlimb ischemia model, and investigate the molecular mechanism underlying the pro-angiogenic effect. CNP were injected into a ligated region of a femoral artery, and tissue reperfusion and hindlimb salvage were monitored for 3 weeks. Tissue analysis revealed stimulation of pro-angiogenic markers, maturation of blood vessels, and remodeling of muscle tissue following CNP administration. At a dose of 0.6 mg CNP, mice showed reperfusion of blood vessels in the hindlimb and a high rate of limb salvage (71%, n = 7), while all untreated mice (n = 7) suffered foot necrosis or limb loss. In vitro, CNP promoted endothelial cell tubule formation via the Ref-1/APE1 signaling pathway, and the involvement of this pathway in the CNP response was confirmed in vivo using immunocompetent and immunodeficient mice and by siRNA knockdown of APE1. These results demonstrate that CNP provide an effective treatment of CLI with excessive ROS by scavenging ROS to improve endothelial survival and by inducing Ref-1/APE1-dependent angiogenesis to revascularize an ischemic limb.Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.