Background: Schizophrenia is a chronic and debilitating psychiatric condition. Although atypical antipsychotics have demonstrated improvements in managing this disorder, conclusive evidence from robust studies remains limited. This study aimed to compare amisulpride and olanzapine in schizophrenia patients with respect to therapeutic efficacy. Materials and Methods: A prospective, randomized, open-label comparative study was conducted. Patients diagnosed with schizophrenia were randomly assigned to two treatment groups. One cohort (n = 78) received olanzapine, while the other cohort (n = 78) was treated with amisulpride. Both groups were followed over 14 weeks. The efficacy of treatments was evaluated using the Positive and Negative Syndrome Scale (PANSS), and the associated costs of antipsychotic medications were analyzed. Results: During the 14-week treatment period, the reduction in positive and negative syndrome scores was 38.51% in the olanzapine group compared to 51.25% in the amisulpride group. The Clinical Global Impression (CGI) score showed a decrease of 54.74% in the olanzapine group and 35.21% in the amisulpride group. The reduction in both scores was greater in the Olanzapine group compared to the Amisulpride group. Conclusion: Both olanzapine and amisulpride resulted in significant reductions in PANSS and CGI scores. However, olanzapine demonstrated superior efficacy compared to amisulpride.