Improving the solubility of pharmaceutical compounds with poor aqueous solubility remains a significant challenge of bioavailability of APIs for product development. Many drugs classified under the Biopharmaceutics Classification System (BCS) Class II experience limited absorption due to slow dissolution rates, necessitating innovative strategies to enhance solubility. These challenges could be ameliorate using the nanocrystal technologies, pure drug nanoparticles stabilized by protective agents, which significantly increase the surface area available for dissolution, thereby improving drug absorption. Nanocrystals can be produced through top-down methods, such as wet milling and high-pressure homogenization, or bottom-up techniques like anti-solvent precipitation. Additionally, hybrid approaches that combine these methods can further refine particle size and improve process efficiency. The QbD framework is integral to the development of nanocrystal formulations that are both stable and effective. By systematically identifying Critical Quality Attributes (CQAs) and optimizing Critical Process Parameters (CPPs), QbD ensures a controlled and reproducible manufacturing process. Important CQAs, such as particle size, polydispersity index, zeta potential, and solid-state characteristics, must be carefully assessed, as they directly impact on drug stability and bioavailability. Critical process parameters (CPPs) such as milling speed, processing time, bead size, stabilizer concentration, and drug load must be meticulously optimized to attain desirable nanocrystal characteristics. This chapter discusses the application of QbD principles in pharmaceutical nano-milling, with a focus on key methodologies, process optimization strategies, and relevant case studies. Establishing a well-defined factorial design and conducting thorough preliminary screening are crucial for determining an optimal design space. As a continuous improvement approach, QbD enhances formulation development, reduces costs, and ensures high-quality drug products that meet regulatory standards.