Organ ischemia with inadequate oxygen supply followed by reperfusion (which initiates a complex of inflammatory responses and oxidative stress) occurs in different clinical conditions and surgical procedures including stroke, myocardial infarction, limb ischemia, renal failure, organ transplantation, free-tissue-transfer, cardiopulmonary bypass, and vascular surgery. Even though pharmacological treatments protect against experimental ischemia reperfusion (I/R) injury, there has not been enough success in their application for patient benefits. The main hurdles in the treatment of I/R injury are the lack of diagnosis tools for understanding the complicated chains of I/R-induced signaling events, especially in the acute phase after ischemia, determining the affected regions of the tissue over time, and then, targeting and safe delivery of antioxidants, drugs, peptides, genes and cells to the areas requiring treatment. Besides the innate antioxidant and free radical scavenging properties, some nanoparticles also show higher flexibility in drug delivery and imaging. This review highlights three main approaches in nanoparticle-mediated targeting of I/R injury: nanoparticles (1) as antioxidants for reducing tissue oxidative stress, (2) for targeted delivery of therapeutic agents to the ischemic regions or cells, and (3) for imaging I/R injury at the molecular, cellular or tissue level and monitoring its evolution using contrasts induced by nanoparticles. These approaches can also be combined to realize so called theranostics for providing simultaneous diagnosis of ischemic regions and treatments by targeted delivery.