To circumvent possible systemic side effects, anti-angiogenic drugs that target vascular endothelial growth factor (VEGF) for the treatment of proliferative ocular diseases are approved only for intravitreal administration. However, intravitreal injection itself can elicit injection-related adverse effects. Premature eyes of infants with retinopathy of prematurity (ROP) may be particularly susceptible to intravitreal injection. Therefore, an unmet clinical need is to develop safe systemic anti-angiogenic therapies for ROP. We recently reported that secretogranin III (Scg3) is a disease-restricted angiogenic factor that binds negligibly to healthy vessels and that systemic anti-Scg3 mAb exerts minimal side effects on developing eyes and organs. Here we analyzed the safety and efficacy of a humanized anti-Scg3 antibody Fab fragment (hFab) delivered by intraperitoneal injection. The results indicate that systemic anti-Scg3 hFab effectively alleviates pathological retinal neovascularization in oxygen-induced retinopathy (OIR) mice, a surrogate model of ROP, with similar efficacy to the anti-VEGF drug aflibercept. Systemic aflibercept conferred significant adverse side effects in neonatal mice, including reduced body weight, abnormalities in retinal and renal development, and retarded physiological neovascularization, whereas systemic anti-Scg3 hFab elicited no such side effects. The findings suggest that systemic anti-Scg3 hFab is a safe and effective therapy for OIR and support further development for ROP treatment.