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The aim of this study was to identify potential developmental toxicity mechanisms of the histone deacetylase inhibitors (HDAC) valproic acid (VPA), suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA) relevant to the <jats:italic>in vivo<\/jats:italic> condition using a hESC model in combination with specific differentiation protocols and genome-wide gene expression and microRNA profiling. Analysis of the gene expression data showed that VPA repressed neural tube and dorsal forebrain (<jats:italic>OTX2<\/jats:italic>, <jats:italic>ISL1<\/jats:italic>, <jats:italic>EMX2<\/jats:italic> and <jats:italic>SOX10<\/jats:italic>)-related transcripts. In addition, VPA upregulates axonogenesis and ventral forebrain-associated genes, such as <jats:italic>SLIT1<\/jats:italic>, <jats:italic>SEMA3A<\/jats:italic>, <jats:italic>DLX2\/4<\/jats:italic> and <jats:italic>GAD2<\/jats:italic>. HDACi-induced expression of miR-378 and knockdown of miR-378 increases the expression of <jats:italic>OTX2<\/jats:italic> and <jats:italic>EMX2<\/jats:italic>, which supports our hypothesis that HDACi targets forebrain markers through miR-378. In conclusion, multilineage differentiation <jats:italic>in vitro<\/jats:italic> test system is very sensitive for monitoring molecular activities relevant to <jats:italic>in vivo<\/jats:italic> neuronal developmental toxicity. 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