On December 22, 2021, the United States Food and Drug Administration approved the first main protease inhibitor, i.e., oral antiviral nirmatrelvir (PF-07321332)/ritonavir (Paxlovid), for the treatment of early severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Nirmatrelvir inhibits SARS-CoV-2 infection, but high doses or long-term treatment may cause embryonic developmental toxicity and changes in host gene expression. The chiral structure of nirmatrelvir plays a key role in its antiviral activity. Ritonavir boosts the efficacy of nirmatrelvir by inactivating cytochrome P450 3A4 expression and occupying the plasma protein binding sites. Multidrug resistance protein 1 inhibitors may increase the efficacy of nirmatrelvir. However, Paxlovid has many contraindications. Some patients treated with Paxlovid experience a second round of coronavirus disease 2019 (COVID-19) symptoms soon after recovery. Interestingly, the antiviral activity of nirmatrelvir metabolites, such as compounds 12–18, is similar to or higher than that of nirmatrelvir. Herein, we review the advances and challenges in using nirmatrelvir and its derivatives with the aim of providing knowledge for drug developers and physicians in the fight against COVID-19.