Objective: To systematically examine the randomized controlled trial (RCT) evidence regarding efficacy and tolerability of topiramate cotreatment with antipsychotics in schizophrenia-spectrum disorders. Methods: Random-effects meta-analysis of RCTs of topiramate cotreatment with antipsychotics vs. placebo/ongoing antipsychotic treatment in schizophrenia-spectrum disorders. Standardized or weighted mean difference (SMD/WMD), risk ratio (RR) ±95% confidence intervals (CIs), and number needed to harm (NNH) were calculated. Results: Across 16 RCTs (n = 934, duration = 11.8 ± 5.6 weeks), topiramate outperformed the comparator regarding change/endpoint of total (SMD: −0.58, 95% CI: −0.82, −0.35, P < 0.00001), positive (SMD: −0.37, 95% CI: −0.61, −0.14, P = 0.002), negative (SMD: −0.58, 95% CI: −0.87, −0.29, P < 0.0001), and general symptoms (SMD: −0.68, 95% CI: −0.95, −0.40, P < 0.00001). Furthermore, topiramate was superior regarding body weight (WMD: –2.75 kg, 95% CI: −4.03, −1.47, P < 0.0001), body mass index (BMI) (WMD: –1.77, 95% CI: −2.38, −1.15, P < 0.00001), triglycerides (P = 0.006), and insulin levels (P < 0.00001). Superiority regarding psychopathology and body weight/BMI was consistent across Chinese/Asian and Western RCTs, double-blind and open designs, clozapine and non-clozapine cotreatment, augmentation and co-initiation RCTs, and higher and lower quality RCTs. In meta-regression analyses, topiramate's efficacy for total symptoms was moderated by shorter illness duration (P = 0.047), while weight loss was greater in prevention/co-initiation vs. intervention/augmentation RCTs (−4.11 kg, 95% CI: −6.70, −1.52 vs. −1.41 kg, 95% CI: −2.23, −0.59, P < 0.001). All-cause discontinuation was similar between topiramate and comparators (RR: 1.28, 95% CI: 0.91, 1.81, P = 0.16). While topiramate led to more concentration/attention difficulties (P = 0.03, NNH = 8, 95% CI=4–25), psychomotor slowing (P = 0.02, NNH = 7, 95% CI = 4–25), and paresthesia (P = 0.05, NNH = 2, 95% CI = 4–33), it led to less ≥7% weight gain (P = 0.0001, NNH = 2, 95% CI = 2–3) and constipation (P = 0.04, NNH = 9, 95% CI = 5–100) than the comparator. Conclusions: These results indicate that adjunctive topiramate to antipsychotics is an effective and safe treatment choice for symptomatic improvement and weight reduction in patients with schizophrenia-spectrum disorders.