Objective To determine the economically justifiable price (EJP) of cenobamate to become a cost-effective alternative compared with third-generation anti-seizure medications in the treatment of focal-onset seizures (FOS) in adult patients with drug-resistant epilepsy (DRE) in Spain. Methods Cost-effectiveness analysis comparing cenobamate with brivaracetam, perampanel, eslicarbazepine acetate and lacosamide. Markov model simulation of treatment pathway over a 60-year time horizon. Determination of effectiveness and quality-adjusted life-years (QALYs) of each health status, and disutilities associated with treatment-related adverse events. Acquisition costs and use of medical resources were obtained from published literature and expert opinion. Base-case of cenobamate’s EJP calculated applying a willingness-to-pay (WTP) threshold of €21,000/QALY. Analyses performed at different thresholds, including dominant price scenario. Results robustness were assessed through sensitivity analyses. Results Base-case shows that cenobamate’s daily EJP of €7.30 is cost-effective for a threshold of €21,000/QALY. At a daily price of €5.45, cenobamate becomes dominant over all treatment alternatives producing cost-savings for the national health system (NHS). Sensitivity analyses supported the robustness of base-case findings. Conclusions Treatment with cenobamate produces incremental clinical benefit over third generation ASMs and at the base-case EJP could represent a cost-effective option for the adjunctive treatment of FOS in adult patients with DRE in Spain.