<p>Tardive dyskinesia (TD) is a persistent, iatrogenic movement disorder arising from long-term use of dopamine receptor antagonists, particularly antipsychotics; however, its clinical and economic impact among adults with schizophrenia remains poorly characterized in real-world settings. This retrospective, matched-cohort analysis used two large U.S. claims databases (PharMetrics Plus and MarketScan Medicaid) to evaluate treatment patterns, healthcare resource utilization (HCRU), and costs among adults with schizophrenia with and without TD. Patients were propensity score matched 1:5 for age, sex, index year, and comorbidity burden. TD was identified in 2.2–2.6% of records, with affected patients being older, more often female, and exhibiting greater medical complexity than those without TD. Following matching, TD was associated with greater use of higher-risk antipsychotic regimens, including nearly double the use of first-generation agents and long-acting injectables, and a twofold to fourfold greater anticholinergic burden. Adherence to antipsychotic therapy was comparable between groups. Across both databases, patients with TD demonstrated substantially greater HCRU and costs, with all-cause expenditures elevated by 56–66% and schizophrenia-related costs by 49–103% versus patients without TD. Approximately one in five individuals with TD received a vesicular monoamine transporter 2 inhibitor, with these patients exhibiting the highest HCRU and costs, suggesting greater disease burden and treatment intensity. TD imposes a considerable clinical and economic burden in schizophrenia underscoring the need for earlier recognition, evidence-based treatment, and preventative strategies, including rational antipsychotic selection and proactive monitoring, to mitigate the long-term impact of TD.</p>