Background: Alzheimer’s disease (AD) is one of the most debilitating diseases in old age, associated with cognitive decline and behavioral symptoms. Objective: This study aimed to investigate the effect of adding mirtazapine to quetiapine in reducing agitation among patients with AD. Methods: Thirty-seven elderly patients (18 cases and 19 controls) with AD, diagnosed according to National Institute on Aging and Alzheimer’s Association (NIA-AA) criteria, were enrolled at Nezam-Mafi Clinic. Inclusion criteria comprised a minimum of two years post-diagnosis, a Cohen-Mansfield Agitation and Aggression Questionnaire (CMAI) score above 45, and treatment with 100–150 mg of quetiapine. Patients were randomly assigned to receive mirtazapine (15 mg at night, increased to 30 mg at night after two weeks) or a placebo. Cognitive changes were assessed at weeks 0 and 6 using the Mini-Mental State Examination instrument. Furthermore, symptoms of agitation and aggression were evaluated using the CMAI questionnaire at weeks 4 and 6. Results: In this study, the mean duration of AD in the control group was 4.68 years, and in the case group, it was 5.05 years. Although the total agitation score showed no significant change at the end of the study compared to the control group, the rate of physical non-aggressive behavior showed a significant decrease (p < 0.05). Conclusions: According to this study, adding mirtazapine to the antipsychotic drug regimen may not be an effective treatment for agitation in AD patients.