Ischemic postconditioning significantly attenuates acute hypoxic-ischemic brain injury caused by cardiopulmonary arrest followed by resuscitation, which can be further divided into rapid and delayed postconditioning, as well as in situ and remote postconditioning, according to the time and location of implementation. This review focuses on the molecular mechanisms underlying the neuroprotective effects of ischemic postconditioning, involving the maintenance of redox balance, regulation of autophagy and energy metabolism homeostasis, reduction of systemic inflammatory responses, as well as suppression of PANoptosis, thus reducing hypoxic-ischemic brain injury through multi-pathway and multi-target molecular networks. Ischemic postconditioning is expected to be a new approach for the clinical treatment of acute hypoxic-ischemic encephalopathy, providing new perspectives for the development of multi-targeting drugs.