Neurological disorders affect billions of people worldwide, with oxidative stress and its associated cellular mechanisms recognized as key pathological drivers of neuronal damage. Despite this, natural agents capable of targeting these mechanisms remain underexplored. Physalis angulata L. (PA) contains physalins and withanolides known for their neuroprotective properties, though its in vivo neuroprotective mechanism remains poorly characterized. This study evaluated the preventive neuroprotective effects of PA leaf extract using an integrated developmental, behavioral, and metabolomic approach in a H₂O₂-induced zebrafish (Danio rerio) model. PA extract demonstrated moderate-to-strong antioxidant capacity (ABTS IC₅₀ = 66.66 ppm; DPPH IC₅₀ = 114.91 ppm). Treatment with 50 ppm PA extract provided optimal neuroprotection, significantly restoring body length, yolk sac utilization, and heart rate, while markedly improving locomotor activity and reducing anxiety-like thigmotaxis behavior. Notably, PA extract demonstrated superior efficacy compared to N-acetylcysteine (NAC) across multiple developmental and behavioral endpoints. Metabolomic profiling of zebrafish embryo homogenates provided direct in vivo biochemical evidence of antioxidant pathway modulation, demonstrating that PA extract mitigated metabolic disruption by restoring amino acid metabolism (glycine, serine, and threonine), glutathione synthesis, glycerophospholipid homeostasis, and one-carbon pool metabolism. These findings demonstrate that P. angulata exerts multi-target neuroprotection by restoring antioxidant pathways and promoting metabolic homeostasis, supporting its potential as a natural therapeutic candidate for oxidative stress-related neurological conditions.