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Abstract Introduction A change of therapy from one to another antipsychotic medication is currently the main challenge of therapy. This study aimed to assess the prevalence of antipsychotic medication switches and determinants among patients with schizophrenia in Northwest Ethiopia. Methods Multi-center hospital-based cross-sectional study was conducted at five Comprehensive Specialized Hospitals found in Northwest Ethiopia from April 30, 2021, to August 30, 2021. Data were extracted from both patients’ medical charts and interviews. Data were entered into Epi-data software version 3.5.1 and exported to SPSS version 25.0 for analysis. A multivariable logistic regression model was fitted to identify factors associated with medication regimen switch. The level of significance of the study was kept at a p-value of 0.05 with a 95% confidence interval. Result A total of 414 patients are involved in the study, and 188 (45.5%) of patients switched antipsychotics within one year. The unavailability of the medication is the commonest reason for switching. Being male [AOR = 2.581, 95% CI (1.463, 4.552)], having relapse [AOR = 2.341,95% CI (1.169,4.687)], history of hospitalization in the past year [AOR = 3.00,95% CI (1.478,5.715)] and taking typical antipsychotics [AOR = 3.340, CI (1.76, 6.00)] had a significant association with antipsychotics switching. Conclusions and recommendations There is a high prevalence of antipsychotic switches among schizophrenia patients. Prescribers need to be careful while dosing, selecting, and switching antipsychotics, hence may help reduce discontinuation and unnecessary switch and thus achieve optimal clinical management.