Hypoxemia after acute myocardial infarction (AMI) causes severe damage to cardiac cells and induces cardiac dysfunction. Protection of cardiac cells and reconstruction of cardiac functions by re-introducing oxygen into the infarcted myocardium represents an efficient approach for the treatment of AMI. However, the established methods for oxygen supplementation mainly focus on systemic oxygen delivery, which always results in inevitable oxidative stress on normal tissues. In this work, an ultrasound (US) activated oxygen generation nanosystem has been developed, which specifically releases oxygen in the infarcted myocardium and alleviates the hypoxemic myocardial microenvironment to protect cardiac cells after AMI. The nanosystem was constructed through the formation of calcium peroxide in the mesopores of biocompatible mesoporous silica nanoplatforms, followed by the assembly of the thermosensitive material heneicosane and polyethyleneglycol. The mild hyperthermia induced by US irradiation triggered the phase change of heneicosane, thus achieving US responsive diffusion of water and release of oxygen. The US-activated oxygen release significantly alleviated the hypoxia and facilitated the mitigation of oxidative stress after AMI. Consequently, the survival of cardiac cells under hypoxic conditions was substantially improved and the damage in the infarcted myocardial tissue was minimized. This US-activated oxygen generation nanosystem may provide an efficient modality for the treatment of AMI.