The article reviews the development of antiviral protein-protein interaction (PPI) inhibitors targeting various viruses, including HIV, SARS-CoV-2, HCV, Ebola, Dengue, and Chikungunya. It highlights the importance of PPI inhibitors as a diverse and valuable strategy in antiviral therapy due to the rapid evolution of viruses. The review discusses three main classes of compounds: antibodies, peptides/peptidomimetics, and small molecules, each with its advantages and disadvantages for drug development. The article provides detailed insights into the mechanisms of action, structural interactions, and clinical progress of these inhibitors, particularly focusing on HIV and SARS-CoV-2. For HIV, the focus is on entry inhibitors targeting gp41 and CD4, while for SARS-CoV-2, the emphasis is on spike protein interactions with ACE2. The article also explores the challenges and advancements in the design and optimization of these inhibitors, including the development of more potent and stable compounds.The article reviews the development of antiviral protein-protein interaction (PPI) inhibitors targeting various viruses, including HIV, SARS-CoV-2, HCV, Ebola, Dengue, and Chikungunya. It highlights the importance of PPI inhibitors as a diverse and valuable strategy in antiviral therapy due to the rapid evolution of viruses. The review discusses three main classes of compounds: antibodies, peptides/peptidomimetics, and small molecules, each with its advantages and disadvantages for drug development. The article provides detailed insights into the mechanisms of action, structural interactions, and clinical progress of these inhibitors, particularly focusing on HIV and SARS-CoV-2. For HIV, the focus is on entry inhibitors targeting gp41 and CD4, while for SARS-CoV-2, the emphasis is on spike protein interactions with ACE2. The article also explores the challenges and advancements in the design and optimization of these inhibitors, including the development of more potent and stable compounds.