<p>While both dopamine type 2 receptor antagonists and the muscarinic M₁R M₁/M₄R agonist xanomeline (KarXT) have shown to be effective in treating positive and total symptoms of schizophrenia, full or partial treatment resistance is common, particularly for negative symptoms and cognitive impairment associated with schizophrenia (CIAS). Based on the concept of targeting excitatory-inhibitory (E/I)-imbalance, serotonin type 3 receptor (5-HT₃R) antagonists may have utility as an adjunctive treatment for residual symptoms in schizophrenia. We present a meta-analysis of 5-HT₃R antagonists (setrons, CVN058 and the antidepressant vortioxetine) for CIAS and negative, positive and total symptoms. 12 active- vs. placebo-arm comparisons across 730 participants met the inclusion criteria. Meta-analyses of both negative symptoms [Cohen’s <i>d</i> = −0.52 (95%CI: −0.78, −0.27), <i>p</i> = 0.012] and CIAS [Cohen’s <i>d</i> = −0.53 (95%CI: 0.09, 0.97), <i>p</i> = 0.02] support a significantly greater effect for active drug at a moderate effect size. The results support the potential utility not only of “setron” type 5-HT₃R antagonists, but also of vortioxetine, which has significant 5-HT₃R antagonist properties along with more general anti-depressant features. Results argue for definitive multicenter studies of adjunctive 5-HT₃R antagonists in schizophrenia.</p>