Lurasidone is a novel antipsychotic agent approved for the treatment of schizophrenia and various mental diseases in many countries. In this study, neuroprotection of Lurasidone by antagonist activities of histamine was investigated in a cranial nerve involvement mouse model. The antagonist activities of Lurasidone for serotonin 5-HT7, serotonin 5-HT2A, serotonin 5-HT1A and dopamine D2 were analyzed and the preclinical therapeutic effects of Lurasidone were studied in a cranial nerve involvement mouse model. This study also assessed safety, maximum tolerated dose (MTD), and preliminary protective activity of Lurasidone in a cranial nerve involvement mouse model. The therapeutic dose was 0.14 mg once daily administered continuously in 30-day cycles. Our results found that our clinical prescriptions induced positive behavioral responses after treatment with Lurasidone. MTD was identified as once daily Lurasidone 0.32 mg. The most common treatment-related treatment-emergent adverse events were proteinuria 30% and nausea 40%. Long-term treatment of Lurasidone for cranial nerve involvement has been shown to better therapeutic effects and reduced anxiety of experimental mice. In addition, treatment of Lurasidone did not affect body weight. Expression of Foxp2 and Neuroglobin was increased and the neuroprotective protein SxIP and EB were decreased in cortical astrocytes cells of the schizophrenia mice after Lurasidone treatment. Lurasidone therapy showed a reinforced memory capability and anxiety decreasing. In conclusion, the Lurasidone treatment may protect against language disturbances associated with negative and cognitive impairments in a cranial nerve involvement mouse model, which provide a basis for clinical treatment of patients with cranial nerve involvement.