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Opuntia joconostle fruit is a rich source of biocompounds such as polyphenols including gallic, vanilic, 4-hidroxybenzoic, cafeic, and syringic acids, catechin, epicatechin, rutin, and vanillin, besides betalains. The objective of this research was to evaluate the effect of supplementation polyphenols-rich extracts from different parts of Opuntia joconostle against carbon tetrachloride-induced oxidative stress in a mouse model. The animals were treated orally with polyphenols-rich extracts at 50, 100 and 200 mg/kg BW for 30 consecutive days. On day 30th the mice received carbon tetrachloride (CCl4) as hepatoxic agent. Biochemical evaluations were carried out 24 h after induction of the oxidative stress. Data showed that methanolic extracts from different parts of Opuntia joconostle exerting protective effect against the CCl4-induced oxidative stress in mice. Histology examination revealed that the damage decreased in groups treated with polyphenols-rich extracts compared to the group that did not receive any treatment. Opuntia joconostle fruit contains many phenolic compounds, flavonoids and betalains. The protective effect of extracts may be related to the phenolic composition and also by a counteraction with other compounds, such as betalains and flavonoids that increase their antioxidant effect.