The increasing demand for new biomaterials and fabrication methods provides an opportunity for silicon to solve current challenges in the field. Laser processing is becoming more common as the public begins to understand its simplicity and value. When an abundant material is paired with a reliable and economic fabrication method, biomedical devices can be created and improved. In this chapter, different laser parameters of the Nd:YAG laser are investigated and the topographic and physical trends are analyzed. The biocompatibility is assessed for scanning speed, line spacing, overlap number, pulse frequency, and laser power with the use of simulated body fluid (SBF) and fibroblast culturing (NIH 3T3). Not only can nanosecond pulses increase the biocompatibility of silicon by generating silicon oxide nanofibers, but the substrate becomes bioactive with the manipulation of cell interactions.