|KCC2 is a K+-Cl- cotransporter with neuronal expression throughout the central nervous system. Deficits in KCC2 activity have been implicated in a variety of neurological disorders, including epilepsy, chronic pain, autism spectrum disorders, and Rett syndrome. Therefore, KCC2 potentiation is a promising conceptual approach to treatment of these disorders. From a translational perspective, it is important to establish if pharmacological potentiation of KCC2 could be therapeutic. However, studies investigating the effect of pharmacological KCC2 potentiation are limited because KCC2 potentiator pharmacology is underdeveloped. Herein, we describe the discovery and characterization of a new class of small molecule KCC2 potentiator, and the evaluation of its effect on in vitro seizure-like activity. This newly discovered class, exemplified by VU0500469 and VU0916219, exhibits KCC2-dependent activity, selectivity versus the structurally related NKCC1 transporter, a unique mechanistic profile relative to known small molecules which enhance KCC2 activity, and increases surface expression of KCC2. Furthermore, we demonstrate that small molecule KCC2 potentiation attenuates seizure-like activity in a neuronal-glial co-culture model of epilepsy. Together, our results provide a unique KCC2 potentiator class useful for deepening the field’s understanding of KCC2 biology, and evidence that pharmacological KCC2 potentiation, by itself, is sufficient to attenuate seizure-like activity. These findings and chemical tools are important for evaluating the promise of KCC2 as a therapeutic target, and could lay a foundation for the development of KCC2-directed therapeutics for multiple neurological disorders with significant unmet medical need.