Small molecules and recombinant proteins are currently applied to modulate relevant cell signaling pathways that can differentiate induced pluripotent stem cells (iPSCs) into specific cell types. Despite the development of several neural differentiation methods, current protocols are labor intensive, inefficient and result in immature cell populations. Improvements to current differentiation protocols are necessary to facilitate the rapid, large-scale production of pure and functionally mature cell types. High-throughput screening combined with automated iPSC differentiation offers a powerful platform for discovery of small molecules that can facilitate neuronal and glial differentiation. Because limited reproducibility, predictability and variability in manual cell culture can affect robustness of high-throughput screens, we developed an automated protocol for controlled differentiation of iPSCs into neural stem cells (NSCs). Using these NSCs, we then screened diverse small molecule libraries at 8 different concentrations in combination with reporter cell lines in order to identify new compounds that can promote neuronal and glial differentiation. Here, we report on the identified lead compounds that induce specific gene and protein expression of neuronal and synaptic markers via epigenetic mechanisms. The use of these chemical compounds may accelerate and improve specification and maturation of human iPSC-derived neural phenotypes.