Background and Purpose: GRIN-related disorders are neurodevelopmental disorders caused by mutations in the N-methyl-D-aspartate receptor (NMDAR) subunit receptor GRIN genes. A large fraction of these mutations leads to gain of function (GoF) of the NMDAR. Patients present with a combination of symptoms that includes epilepsy, intellectual disability, behavioural and motor symptoms. Controlling seizures is a significant medical need in most patients with GRIN-related disorders. The aim of this study was to assess the therapeutic efficacy of radiprodil, a selective negative allosteric modulator of GluN2B-containing NMDARs, in counteracting audiogenic seizures (AGS) in a murine model carrying the GluN2A(N615S) mutation in homozygosity (Grin2aS/S mice). Experimental Approach: Grin2aS/S mice were acutely treated with radiprodil at different doses before the presentation of a high-frequency acoustic stimulus commonly used for AGS induction. Key Results: Radiprodil significantly and dose-dependently reduced the onset and severity of AGS in Grin2aS/S mice. Conclusion and Implications: Our data clearly indicates that radiprodil has the potential to control seizures in patients with GRIN2A GoF mutations, targeting the underlying pathophysiology of the disorder.