Background. The Anacardium occidentale L. (cashew) and Anacardium microcarpum D. (cajuí) are plants commonly found in Brazil. They present phytochemical compounds with antioxidant and anti-inflammatory action. Therefore, the objective of this study was to analyze the antioxidant and anti-inflammatory activities of ethanolic extracts from leaves of A. occidentale and A. microcarpum and its effect on the hepatic tissue in experimental knockout models after they received Paracetamol®. Methods. Ethanol extracts from A. occidentale and A. microcarpum leaves were prepared. Total phenolics were determined by Folin–Ciocalteau reagent, and flavonoids are based on the complexation reaction with the aluminum metal, forming a colored complex. Fingerprint HPLC was performed to detect phenolic compounds. Knockout IL-10 mice randomly divided into six groups were used and received the following treatments: G1, only water; G2, A. occidentale extract; G3, A. microcarpum extract; G4, Paracetamol®; G5, Paracetamol® + A. occidentale extract (400 mg/kg); G6, Paracetamol® + A. microcarpum extract (400 mg/kg). Biochemical parameters of the blood and differential count of leukocytes were done. Oxidative markers and histopathological analyses were performed on their liver tissue. Results. Phenolic compounds and total flavonoids were detected in both two extracts analyzed. The HPLC fingerprint detected phenolic acid, gallic acid, and catechin flavonoid in the two extracts. Histopathological analyses of the hepatic tissue permitted evaluation of nuclear increase, sinusoid congestion, and inflammatory infiltrate. A. microcarpum presented more antioxidant activity increasing antioxidant enzyme levels and reducing TBARS and carbonyl protein when compared to the other treatments after exposure to Paracetamol®. Histopathological analyses showed a decrease in the inflammatory infiltrate after treatment with extracts. Conclusion. Our findings indicate that both extracts, especially A. microcarpum, can reduce hepatic damage in knockout mice exposed to paracetamol, indicating the curative power of these extracts reducing lipid peroxidation and in the morphofunctional damage to the liver parenchyma.