Peptides and peptidomimetic-basedPeptidomimetics inhibitors occupy a pivotal therapeutic middle ground between small-molecule inhibitors and antibodies, offering an unique advantage in drug design by effectively targeting flat and large protein–protein interaction surfaces. As computational toolsComputational tools continue to advance through the integration of Machine LearningMachine learning and Artificial Intelligence, it has become indispensable in designing and developing potential peptide and peptidomimetic-based drug candidates. Computational toolsComputational tools can be employed throughout various stages of drug discovery, including the design, simulation of protein–protein interaction, physicochemical characterization, and toxicological profiling, among others. This chapter introduces the nature of protein–protein interaction and the utility of peptides and peptidomimetic-based inhibitors for inhibiting these interactions, followed by their limitations and prospects. We further showcase the computational aspects of developing various peptide and peptidomimetic-based inhibitors, including their challenges and therapeutic promises.