A novel processing method is described using photolithography to pattern thin-film flexible electronics on shape memory polymer substrates with mechanical properties tailored to improve biocompatability and enhance adhesion between the polymer substrate and metal layers. Standard semiconductor wafer processing techniques are adapted to enable robust device design onto a variety of softening substrates with tunable moduli. The resulting devices are stiff enough (shear modulus of similar to 700 MPa) to assist with device implantation and then soften in vivo (similar to 300 kPa) approaching the modulus of brain tissue (similar to 10 kPa) within 24 h. Acute in vivo studies demonstrate that these materials are capable of recording neural activity. Softening multi-electrode arrays offer a highly customizable interface, which can be optimized to improve biocompatibility, enabling the development of robust, reliable neural electrodes for neural engineering and neuroscience.