This study aimed at determining hepatoprotective and antioxidants effects of Lactarius deliciosus and Agrocybe cylindracea against CCl4-induced oxidative stress (OS) in rats. Herein, 36 rats were divided into 6 groups: (I) Control, (II) CCl4, (III) CCl4 + L. deliciosus, (IV) L. deliciosus, (V) CCl4 + A. cylindracea, and (VI) A. cylindracea. According to the 7-week study results, aspartate aminotransferase (AST), alanine aminotransferase (ALT), glutathione S-transferase (GST) (brain), superoxide dismutase (SOD) (kidney), malondialdehyde (MDA) (kidney), MDA (spleen), MDA (erythrocyte), GST (erythrocyte), and GST (liver) in group III (at 10%, 26%, 34%, 57%, 7%, 25%, 42%, 27%, and 35%, respectively) were significantly lower than in group II. Moreover, the reduced glutathione (GSH) (spleen) and catalase (spleen) in group III (at 20% and 38%, respectively) were significantly higher than in group II. AST, ALT, tri-glyceride, glutathione reductase (GR) (brain), GR (kidney), SOD (spleen), and SOD (liver) in group V (at 194%, 147%, 38%, 36%, 66%, 8%, and 7%, respectively) were significantly higher than in group II. However, MDA (kidney), MDA (erythrocyte), (GSH) (erythrocyte), MDA (liver), GSH (liver), and GST (liver) in group V (at 48%, 35%, 34%, 15%, 30%, and 41%, respectively) were significantly lower than in group II. Hence, while L. deliciosus may exhibit tissue-pro-tective against CCl4-induced OS in rats, A. cylindracea does not.