Lennox–Gastaut Syndrome (LGS) is a developmental and epileptic encephalopathy (DEE) characterized by multiple seizure types, electroencephalogram (EEG) patterns, and cognitive decline. Its etiology has a prominent genetic component, including variants inGABRB3that encodes the GABAAreceptor (GABAAR) β3subunit. LGS has an unknown pathophysiology, and few animal models are available for studying LGS. The objective of this study was to evaluateGabrb3+/N328Dknock-in mice as a model for LGS. We generated a heterozygous knock-in mouse expressingGabrb3(c.A982G, p.N238D), a de novo mutation identified in a patient with LGS. We investigatedGabrb3+/N328Dmice for features of LGS. In 2–4-month-old male and female C57BL/J6 wild-type andGabrb3+/N328Dmice, we investigated seizure severity using video-monitored EEG, cognitive impairment using a suite of behavioral tests, and profiled GABAAR subunit expression by Western blot.Gabrb3+/N328Dmice showed spontaneous seizures and signs of cognitive impairment, including deficits in spatial learning, memory, and locomotion. Moreover,Gabrb3+/N328Dmice showed reduced β3subunit expression in the cerebellum, hippocampus, and thalamus. This phenotype of epilepsy and neurological impairment resembles the LGS patient phenotype. We conclude thatGabrb3+/N328Dmice provide a good model for investigating the pathophysiology and therapeutic intervention of LGS and DEEs.