BACKGROUND AND HYPOTHESIS: Antipsychotic use in severe mental illnesses (SMI) is associated with metabolic dysregulation, including antipsychotic-induced weight gain (AIWG), type 2 diabetes (T2D), and dyslipidemia. In the case of non-response to metformin which is currently recommended for AIWG mitigation, no clear alternatives exist. Semaglutide, a weekly injectable glucagon like peptide-1 receptor agonist, represents a promising option. However, effectiveness and safety data in SMI are lacking. With initiation of semaglutide, we hypothesized weight loss, improvements in metabolic indices, and good tolerability. STUDY DESIGN: A retrospective chart review was conducted for inpatients receiving antipsychotics, initiated on once-weekly subcutaneous semaglutide between January 4, 2018 and March 31, 2024 at the Centre for Addiction and Mental Health in Toronto, Canada, that analyzed weight loss, metabolic parameters, and side effects. STUDY RESULTS: 47 individuals with SMI were included: 59.6% males, mean age of 43 ± 13.2 years, 83% had dysglycemia, and 66% had T2D at baseline. The maximum dose of semaglutide in this cohort was 2 mg/week. There was a mean weight loss of 3.15 ± 0.77 kg (n = 47), 7.27 ± 0.97 kg (n = 24), 9.33 ± 1.16 kg (n = 15), and 12.25 ± 1.32 kg (n = 11) at 3, 6, 9, and 12 months, respectively (P < .001). Individuals without T2D experienced greater weight loss versus those with T2D (P = .022). Additionally, significant decreases were noted in body mass index and HbA1c (P < .001), alongside improvements in lipid parameters; most common side effects were gastrointestinal in nature but did not result in semaglutide discontinuation. CONCLUSION: This retrospective chart review of inpatients with SMI supports efficacy and safety of semaglutide up to a year of follow-up, warranting future adequately powered randomized controlled trials.