Artificial biomimetic substrates provide useful models for studying cell adhesion, signaling, and differentiation. This article describes biological interactions with a new type of tunable, micro-nanotextured silicon substrate, generated by irradiation of a hydrogenated amorphous silicon film with a large beam, excimer laser (248 nm). In this study, we demonstrate that BV-2 microglial cells can sense differences in laser processed silicon surface topology over the range of 30 nm to 2 μm, where they undergo marked morphogenic changes with increasing feature size. The cells adopt a more elongated shape in the presence of the modified surface structure and exhibit increased levels of actin-rich microdomains, suggesting enhanced adhesion. The excimer laser modification of hydrogenated amorphous silicon to generate micro-nanostructures realizes large area benefits as well as providing a biomaterial where the external and internal structure can be altered and tuned for various applications.