Ischemia-related processes associated with generation of inflammatory molecules such as reactive oxygen species (ROS) are difficult to detect at the acute stage before physiologic and anatomic evidence of tissue damage is present. Evaluation of the inflammatory and healing response early after an ischemic event in vivo will aid in treatment selection and patient outcomes. We introduce a novel near-infrared hydrocyanine molecular probe for detection of ROS as a marker of tissue response to ischemia and a precursor to angiogenesis and remodeling. The synthesized molecular probe, initially a non-fluorescent hydrocyanine conjugated to polyethyleneglycol, converts to a highly fluorescent cyanine reporter upon oxidation. The probe was applied in a preclinical mouse model for myocardial infarction, where ligation and removal of a portion of the femoral artery in the hindlimb resulted in temporary ischemia followed by angiogenesis and healing. The observed increase in fluorescence intensity was approximately 6-fold over 24 h in the ischemic tissue relative to the uninjured control limb and was attributed to the higher concentration of ROS in the ischemic tissue. These results demonstrate the potential for non-invasive sensing for interrogating the inflammatory and healing response in ischemic tissue.