Retinal ischemia–reperfusion (RIR) injury caused by high intraocular pressure (IOP) is an important risk factor contributing to retinal ganglion cell (RGC) death, eventually causing blindness. A key progressive pathological process in the development of RIR is the death of RGCs. However, the detailed mechanisms underlying RGC death caused by RIR have not yet been clearly elucidated, and effective treatments are lacking. Ferroptosis is a recently defined form of programmed cell death that is closely related to organ injury. Melatonin (MT) is a promising neuroprotective agent, but its effects on RIR injury remain unclear. In this study, murine models of acute ocular hypertension and oxygen and glucose deprivation/reoxygenation (OGD/R) model were adopted to simulate retinal ischemia. MT alleviated retinal damage and RGC death in RIR mice, significantly attenuating RIR–induced ferroptosis. Furthermore, MT reduced the expression of p53, a master regulator of ferroptosis pathways, and the upregulation of p53 promoted ferroptosis and largely abolished the neuroprotective effects of MT. Mechanistically, the overexpression (OE) of p53 suppressed the expression of the solute carrier family 7 member 11 (Slc7a11), which was accompanied by increased 12–lipoxygenase (Alox12) expression, triggering retinal ferroptosis. Moreover, MT–ameliorated apoptosis, neuroinflammation and microglial activation were observed. In summary, MT conferred neuroprotection against RIR injury by inhibiting p53–mediated ferroptosis. These findings indicate that MT is a retina–specific ferroptosis inhibitor and a promising therapeutic agent for retinal neuroprotection.