A combined small-molecule treatment accelerates the maturation of human pluripotent stem cell (hPSC)-derived neurons. The study identifies a cocktail of four compounds—GSK2879552, EPZ-5676, N-methyl-D-aspartate, and Bay K 8644—termed GENtoniK—that significantly enhances neuronal maturation across multiple parameters, including synaptic density, electrophysiology, and transcriptomics. This cocktail was validated in various cell types, including cortical organoids, spinal motoneurons, melanocytes, and pancreatic β-cells, indicating that mechanisms controlling human maturation timing may be shared across lineages. The maturation process was assessed using a high-content imaging assay that monitors multiple features of neuronal maturation, including dendritic outgrowth, nuclear size and morphology, and IEG expression. The study also identified that the maturation of hPSC-derived neurons is slow and influenced by species-specific molecular clocks, which are particularly slow in human neurons. The combination of compounds targeting chromatin remodeling and calcium-dependent transcription was found to be effective in accelerating maturation. The study further shows that GENtoniK promotes functional maturation in non-neuronal lineages, including melanocytes and pancreatic β-cells. The results suggest that GENtoniK provides a simple and effective strategy to accelerate maturation timing in neuronal and some non-neural cell types. The study highlights the importance of understanding the molecular mechanisms underlying neuronal maturation and the potential of small-molecule treatments to enhance this process.A combined small-molecule treatment accelerates the maturation of human pluripotent stem cell (hPSC)-derived neurons. The study identifies a cocktail of four compounds—GSK2879552, EPZ-5676, N-methyl-D-aspartate, and Bay K 8644—termed GENtoniK—that significantly enhances neuronal maturation across multiple parameters, including synaptic density, electrophysiology, and transcriptomics. This cocktail was validated in various cell types, including cortical organoids, spinal motoneurons, melanocytes, and pancreatic β-cells, indicating that mechanisms controlling human maturation timing may be shared across lineages. The maturation process was assessed using a high-content imaging assay that monitors multiple features of neuronal maturation, including dendritic outgrowth, nuclear size and morphology, and IEG expression. The study also identified that the maturation of hPSC-derived neurons is slow and influenced by species-specific molecular clocks, which are particularly slow in human neurons. The combination of compounds targeting chromatin remodeling and calcium-dependent transcription was found to be effective in accelerating maturation. The study further shows that GENtoniK promotes functional maturation in non-neuronal lineages, including melanocytes and pancreatic β-cells. The results suggest that GENtoniK provides a simple and effective strategy to accelerate maturation timing in neuronal and some non-neural cell types. The study highlights the importance of understanding the molecular mechanisms underlying neuronal maturation and the potential of small-molecule treatments to enhance this process.