The study addresses the challenge of accelerating the maturation of human pluripotent stem cell (hPSC)-derived neurons, which is crucial for modeling and treating neurological diseases. A high-content imaging assay was designed to monitor multiple parameters of neuronal maturation, including dendritic outgrowth, nuclear size and morphology, and excitability. Through a chemical screen, a cocktail of four compounds (GENtoniK) was identified that effectively accelerated maturation across various parameters, including synaptic density, electrophysiology, and transcriptomics. GENtoniK was validated in cortical organoids, spinal motoneurons, and non-neural lineages such as melanocytes and pancreatic β-cells. The cocktail targets chromatin remodeling and calcium-dependent transcription, with potential mechanisms involving histone demethylation, histone methylation, and calcium signaling. The study highlights the importance of understanding the epigenetic programs that prevent rapid maturation in human neurons and suggests that GENtoniK can be a promising strategy to enhance maturation in both neuronal and non-neuronal cell types.The study addresses the challenge of accelerating the maturation of human pluripotent stem cell (hPSC)-derived neurons, which is crucial for modeling and treating neurological diseases. A high-content imaging assay was designed to monitor multiple parameters of neuronal maturation, including dendritic outgrowth, nuclear size and morphology, and excitability. Through a chemical screen, a cocktail of four compounds (GENtoniK) was identified that effectively accelerated maturation across various parameters, including synaptic density, electrophysiology, and transcriptomics. GENtoniK was validated in cortical organoids, spinal motoneurons, and non-neural lineages such as melanocytes and pancreatic β-cells. The cocktail targets chromatin remodeling and calcium-dependent transcription, with potential mechanisms involving histone demethylation, histone methylation, and calcium signaling. The study highlights the importance of understanding the epigenetic programs that prevent rapid maturation in human neurons and suggests that GENtoniK can be a promising strategy to enhance maturation in both neuronal and non-neuronal cell types.