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This study is sought to determine the antioxidant activity and protective ability of aqueous and methanol extractible phytochemicals from Euphorbia heterophylla leaves on lipid peroxidation induced in rat brain by pro-oxidant, in vitro. The extracts of the leaves were prepared, and the ability of the extracts is to inhibit 25 µM FeSO4 induced lipid peroxidation in isolated rats’ brain, were determined. Thereafter, total phenol content, reducing power (FRAP), Fe (II) chelating, and DPPH* free radical scavenging ability of the extracts was determined and considered as an index of antioxidant activity. The results revealed that the extracts inhibit malondialdehyde (MDA) production in the basal and pro-oxidant induced lipid peroxidised rats in a dose-dependent manner, [methanol 80.11%, aqueous 70.3%] with the methanol extract (MEE) significantly (P< 0.05) than that of aqueous extract (AEE). The methanol extract (0.74 ± 0.6 mg/g) had higher total phenol contents than the aqueous (0.57 ± 1.2 mg/g); likewise the methanol extract had higher reducing power (0.08 ± 0.2, 0.03 ± 0.1 mg/g), but had no significant difference in Fe (II) chelating ability (EC50= 0.34, 0.36) with DPPH* scavenging ability (EC50=0.075, 0.075). This antioxidant properties and the protective effect of this leaf could be harnessed in the management and prevention of degenerative diseases in association with oxidative stress.