Schizophrenia is one of the psychotic mental disorders characterized by symptoms of thought, behavior, and social problems. Newer biomedicine and pharmacotherapy has been investigated for the treatment of various neuropsychiatric disorders in the past few decades. Spinacia oleracea is one of these, reported to have beneficial effect against several neurodegenerative disorders. The present study was carried to explore the protective effects of Spinacia oleracea seed extract (SOEE) in an experimental model of ketamine-induced schizophrenia in mice. Ketamine (50 mg/kg, i.p.) was used to induce stereotyped psychotic behavioural symptoms in mice. Behavioral studies (locomotor activity, stereotype behaviors, immobility duration and memory retention) were carried out to investigate the protective of SOEE on ketamine-induced psychotic symptoms, followed by biochemical, neurochemical and cellular alterations in the brain. Treatment with SOEE for 15 consecutive days significantly attenuated stereotyped behavioral symptoms in mice. Biochemical estimations revealed that SOEE reduced lipid peroxidation and restored total brain proteins. Furthermore, SOEE remarkably reduced dopamine levels, AChE activity & inflammatory surge (serum TNF-α) and increased the levels of GABA and reduced glutathione in mice. The outcomes of the study suggested that SOEE could ameliorate ketamine-induced psychotic symptoms in mice, indicating a protective effect in the treatment of schizophrenia.