Abstract Background Schizophrenia is a complex psychiatric disorder characterized by positive, negative, and cognitive symptoms. KarXT, a novel combination of xanomeline and trospium, offers potential therapeutic benefits for schizophrenia treatment by targeting muscarinic receptors and avoiding dopamine receptor blockade. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of KarXT. Methods PubMed, Scopus, Web of Science, and Cochrane databases were systematically searched for relevant randomized controlled trials (RCTs) up to October 2024. Studies involving adult patients with schizophrenia treated with KarXT were included. Furthermore, the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was used to assess evidence quality, and the risk of bias was evaluated using the Cochrane Risk of Bias 2.0 tool. Results Four studies with 690 participants were included. KarXT significantly reduced Positive and Negative Syndrome Scale (PANSS) total scores compared to placebo (mean difference (MD): -13.77, 95% confidence interval (CI) [-22.33 to -5.20], P-value = 0.002), with significant improvements in positive and negative subscale scores. It significantly increased the incidence of achieving ≥ 30% PANSS score reduction (risk ratio: 2.15, 95% CI [1.64 to 2.84], P