Freeze-drying, also known as lyophilization, is a revolutionary technique in the development of pharmaceutical and biomedical products, particularly for stabilizing sensitive compounds. Historically used for parenteral formulations, recent advancements have expanded its application to oral drug delivery, effectively tackling issues related to stability, bioavailability, and patient compliance. This chapter delves into the core principles of freeze-drying and emphasizes the importance of critical material attributes (CMAs) and critical process parameters (CPPs) for optimizing the freeze-drying process. The shift from parenteral to oral formulations has led to the development of innovative products such as orally disintegrating tablets (e.g., Zydis, Lyoc), probiotics, oral vaccines, and nanocrystal-based systems. Emerging applications like mucoadhesive delivery systems and self-nanoemulsifying lyophilized tablets (SNELTs) showcase the versatility of this technology. Despite facing challenges, such as high costs, complexity, and scalability issues, freeze-drying continues to advance, providing new solutions for oral drug delivery and other applications. This chapter offers a thorough overview of its uses in oral drug delivery, current obstacles, and future potential.