Background: Impaired cognitive flexibility is the core manifestation of schizophrenia (SZ). Previous literature raised a claim against the effect of atypical antipsychotic drugs (AAD) on cognitive and executive functions whose cause needs further investigation. Attention set-shifting task (ASST) tests the prefrontal cortex's (PFC) executive and flexibility functions. Goals: To examine Olanzapine (OLZ) effect on ASST, expression of N-methylD-aspartate receptor 1 (NMDR-NR1) in prefrontal cortex (PFC), and metabolic comorbidity in ketamine (KET) model of SZ. Methods: Sixty-two male rats were divided into three groups: 8 for ASST and 30 for open field, ELISA and immunohistochemistry sub-chronic study, and 24 for regular serological and histopathological examination. Rats treated with V; vehicle; K: KET and KO: OLZ plus KET. Results: KET caused significant increase in time, trials, and errors to reach criterion. OLZ co-administration reversed effects of KET in ASST with no reduction of locomotor activity. OLZ normalized KETinduced rise of NR1 expression and protected against KET-induced degenerative changes in hippocampus and PFC Significant increase in serum liver enzymes, total bilirubin, and lipids with chronic compared to sub-chronic OLZ administration. In contrast, insignificant difference between sub-chronic OLZ and vehicle was found. Conclusions: Current study demonstrated the efficacy of OLZ to reverse KET-induced cognitive deficits in ASST with neither reduction in NR1 expression in PFC nor metabolic malfunction in the sub-chronic study. It also showed the protective effect of OLZ on KET induced neuronal degeneration and necrosis. We suggest that chronic OLZ treatment-inducedmetabolic malfunction might be the cause of time-dependent cognitive deterioration.