Inroduction & Objective: Fluoxetine is a selective inhibitor of serotonin reabsorption (SSRI), and is used as the first-line drug against depression and many other mental-psychological disorders. It induces impairment in the levels of hepatic enzymes as well as histological damages. In the present study, the protective effects of spinach hydro-alcoholic extract on hepatic histology and functions were investigated following administration of fluoxetine to adult male rats. Material and Methods: 50 adult male Wistar rats were randomly divided in 5 groups: (1) the control group left untreated, the positive control receiving 120mg/kg bw fluoxetine, The negative control receiving 200 mg/kg bw spinach extract and the experimental groups 1 and 2 first received 100 and 200 mg/kg spinach extract respectively, and then 120 mg/kg bw Fluoxetine for 21 days. At the end of this period, animals were weighed and blood samples were taken from their hearts. These samples were used for measurement of serum levels of ALT, AST, ALP, GGT, total protein, albumin and total bilirubin. At the end of the test, remove the liver completely in the abdominal cavity. After weighing the liver, place it in a container containing 10% formalin until the specimens are fixed and ready to be crossed. Results: In comparison to the control and the negative control, serum levels of ALT, AST, ALP, GGT and total bilirubin showed a significant increase in the positive control group receiving fluoxetine alone. Also, animals of positive control showed a decrease in serum levels of albumin and total protein. Consumption of spinach extract alone had no significant effect on the serum levels of ALT, AST, ALP, GGT, total bilirubin, albumin, total protein relative to the control group, While consumption of this extract in experimental groups 1 and 2 reduced hepatic toxicity induced by fluoxetine (p < 0. 05) Compared to control and control groups, the fluoxetine recipient alone caused cellular damage in the liver tissue. The consumption of spinach extract alone did not significantly alter the liver tissue compared to the control group, while the extract recipient groups reduced fluconazole-induced liver toxicity. Conclusion: According to the results, spinach extract has a considerable protective effects against fluoxetine side effects on the liver, and can improve, hepatic functions and liver tissue damages.