Objective Lamotrigine is a commonly prescribed antiepileptic drug. U.S. Food and Drug Administration (FDA)–funded clinical studies have demonstrated bioequivalence (BE) for generic lamotrigine immediate‐release (IR) products in epilepsy patients with generic substitution. To address the potential concerns about the risk of generic‐brand substitution of lamotrigine extended‐release (ER) products, considering the complexity of controlled release systems and pharmacokinetic variations associated with possible within‐subject variability (WSV), this prospective study assessed (1) BE of generic and brand lamotrigine ER products in a fully replicated BE study design in healthy subjects and (2) whether such fully replicated study design and WSV data can better support the approval of generic lamotrigine ER products. Methods This open‐label, single‐dose, two‐treatment, four‐period, two‐sequence, fully replicated crossover BE study compared generic lamotrigine ER tablet to brand Lamictal XR (200 mg) in 30 healthy subjects under fed conditions. Pharmacokinetics (PK) profiles were generated based on intensive blood sampling up to 144 h. Results The two products showed comparable peak plasma concentration (Cmax), area under the concentration‐time curve (AUC) from time zero to the last measurable time point (AUC0‐t) and AUC extrapolated to infinity (AUC0‐inf), whereas median time to Cmax (Tmax) values differed, that is, 10 h for generic and 22 h for brand products, respectively. WSVs for PK metrics were small (~8% of Cmax and ~6% of AUC) and similar between these two products. PK simulation predicted equivalent PK measurements of both products at steady state and after brand‐to‐generic switch, except the first day upon switching. No serious adverse events were reported. Significance The generic lamotrigine ER tablet product demonstrates BE to the brand product in a fully replicated BE study design with healthy subjects, supporting the adequacy of the two‐way crossover study design to demonstrate BE and generic‐brand substitution of lamotrigine ER products.