The study investigated the expression of the CYP46A1 enzyme and the effect of its activation by the drug efavirenz in the developing mouse retina. Seven-day-old C57BL/6J mice were either housed under normal conditions or exposed to an oxygen-induced retinopathy (OIR) model, and treated with 20 mg/kg efavirenz intraperitoneally from P7 to P17. Efavirenz significantly reduced pathological neovascularization, the size of avascular and hypoxic areas in the retina of mice with OIR. In addition, the treatment reduced reactive Müller cell gliosis and microglial activation. Efavirenz improved retinal ganglion cell survival in mice with OIR. These effects are partially due to the activation of CYP46A1, which ameliorated the key pathological features of the OIR model.