Abstract: With high target selectivity and biological activity, protein and peptide drugs have been widely applied in the clinical treatment of major diseases such as diabetes and tumors. However, the oral bioavailability of these drugs is mostly less than 1%, and injection still remains the dominant clinical route of administration. In recent years, oral delivery technology has provided a feasible approach for the non-invasive administration of protein and peptide drugs, however, the main limiting factors for oral delivery vary among different protein and peptide drugs and often change depending on their molecular characteristics as well as in vivo disposal processes including absorption, distribution and clearance. Optimization the process for a single absorption barrier alone makes it difficult to steadily enhance and precisely modulate oral bioavailability. This review analyzes the in vivo behaviors of orally administered protein and peptide drugs from the perspectives of absorption, distribution and clearance, summarizes the underlying mechanisms restricting their oral absorption efficiency, and clarifies the applicable ranges and conditions for various delivery strategies, aiming to provide some theoretical reference for the rational design and clinical translation of oral formulations of protein and peptide drugs.