Oral nanodrug delivery systems have gained prominence in pharmaceutical research due to their high safety, excellent patient compliance, and significant clinical translation potential. However, the multiple physiological barriers of the gastrointestinal tract severely limit the absorption of peptide/protein-based biologics, resulting in low bioavailability. Nanotechnology-based delivery systems can enhance gastrointestinal permeability and drug stability, enabling site-specific accumulation while minimizing off-target effects. Recent advances have demonstrated remarkable progress in treating gastrointestinal diseases (e.g., inflammatory bowel disease) and have provided novel non-invasive therapeutic strategies for systemic disorders such as diabetes and cancer. This review systematically elucidates the mechanisms of gastrointestinal barriers and their impacts on drug delivery, cutting-edge advancements in nanocarriers for treating digestive and systemic diseases, and key challenges in clinical translation, aiming to provide a theoretical foundation and future perspectives for advancing oral nanomedicines.