Insulin is currently available as an injectable formulation, but an oral product would enjoy higher patient compliance and would significantly improve the quality of life of diabetic patients worldwide. However, oral delivery of proteins such as insulin is challenging due to various gastrointestinal barriers to oral absorption of macromolecules. We have developed a safe and highly effective ionic liquid-based oral insulin formulation that significantly enhanced oral insulin absorption by efficiently circumventing the gastrointestinal barriers. Besides, the formulation demonstrated good stability at room temperature and under refrigeration. Evidence from cell and animal studies supports a promising prospect of development of the formulation into a clinical product.