Proper intracellular Cl concentration is fundamental for physiological brain development and function. Accordingly, the aberrant expression of the Cl importer NKCC1 and exporter KCC2 is implicated in several brain conditions, including Down syndrome (DS) and autism spectrum disorders (ASD). Interestingly, NKCC1 inhibition rescues core symptoms of these conditions in rodent models and/or clinical trials. However, current NKCC1 inhibitors have diuretic effects by also inhibiting the kidney Cl transporter NKCC2. Excessive diuresis creates critical health, drug compliance and dosage concerns, strongly jeopardizing the current unselective NKCC1 inhibitors from becoming a viable therapy for long-term chronic treatments. Selective NKCC1 inhibitors would be devoid of diuretic effects, thus solving all related health, compliance and dosing issues. To this aim, we performed library screening and rational drug design supported by computational methods to search for novel and selective NKCC1 inhibitors, which we tested in several cell-based assays in vitro and in mouse models of neurodevelopmental disorders. Here, we present the discovery of a new class of selective NKCC1 inhibitors obtained by this extensive drug discovery effort. Lead compound IAMA-6 have a favorable drug-like profile. IAMA-6 was able to recover cognitive deficits in DS mice and core behaviors in ASD mice, without showing any diuretic effect. IAMA-6 proved selective and safe, showing neither any significant off-target in vitro nor leading to any histopathological alterations in vivo. Thus, IAMA-6 represents a solid lead compound ready for advanced preclinical studies toward its development into a clinically relevant drug for unprecedented sustainable pharmacological therapeutics in DS and ASD. Currently in the discovery phase, new classes of selective NKCC1 inhibitors will expand our pipeline of compounds to treat additional and diverse brain conditions characterized by defective NKCC1/KCC2 expression.