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Biophysical cues, such as nanotopography, have been shown to be integral for tissue regeneration and embryogenesis in the stem cell niche. Synthetic nanostructures can drive specific cell differentiation, but the sensing mechanisms for nanocues remain poorly understood. Here, we report that nanotopography-induced human mesenchymal stem cell (hMSC) differentiation through cell mechanotransduction is modulated by the integrin-activated focal adhesion kinase (FAK). On 250 nm nanogratings on polydimethylsiloxane, hMSCs developed aligned stress fibers and showed an upregulation of neurogenic differentiation markers. In addition, our mechanistic study confirmed that this regulation was dependent upon actomyosin contractility, suggesting a direct force-dependent mechanism. FAK phosphorylation was required for topography-induced hMSC differentiation while FAK overexpression overruled the topographical cues in determining cell lineage bias. The results indicated that FAK activity had a direct impact on topography-induced gene expression. These findings suggest that hMSC sense and transduce nanotopo-graphical signals through focal adhesions and actomyosin cytoskeleton contractility to induce differential gene expression.