The article provides a comprehensive overview of Paxlovid, a combination drug used to treat COVID-19, consisting of nirmatrelvir and ritonavir. Nirmatrelvir is a reversible covalent peptidomimetic inhibitor of the main protease (Mpro) of SARS-CoV-2, which plays a crucial role in viral replication. Ritonavir, on the other hand, serves as a pharmacokinetic enhancer by irreversibly inhibiting the CYP3A4 enzyme, which metabolizes nirmatrelvir, thereby increasing its half-life and bioavailability. The article details the development and synthesis of both components, including the design of the nitrile warhead in nirmatrelvir and the synthesis of ritonavir. It also discusses the efficacy of Paxlovid against novel virus mutants and its potential drug-drug interactions. The review highlights the importance of protease inhibitors as antiviral drugs and the ongoing research into novel Mpro inhibitors to combat future pandemics.The article provides a comprehensive overview of Paxlovid, a combination drug used to treat COVID-19, consisting of nirmatrelvir and ritonavir. Nirmatrelvir is a reversible covalent peptidomimetic inhibitor of the main protease (Mpro) of SARS-CoV-2, which plays a crucial role in viral replication. Ritonavir, on the other hand, serves as a pharmacokinetic enhancer by irreversibly inhibiting the CYP3A4 enzyme, which metabolizes nirmatrelvir, thereby increasing its half-life and bioavailability. The article details the development and synthesis of both components, including the design of the nitrile warhead in nirmatrelvir and the synthesis of ritonavir. It also discusses the efficacy of Paxlovid against novel virus mutants and its potential drug-drug interactions. The review highlights the importance of protease inhibitors as antiviral drugs and the ongoing research into novel Mpro inhibitors to combat future pandemics.