Purpose <p>To compare the effectiveness and safety of two antiviral drugs, azvudine and nirmatrelvir/ritonavir, in treating hospitalized patients with COVID-19.</p> Methods <p>We conducted a retrospective analysis of patients who were admitted to the First Affiliated Hospital of Soochow University and diagnosed with SARS-CoV-2 infection between December 2022 and February 2023. These patients were treated with either azvudine or nirmatrelvir/ritonavir.</p> Results <p>The study initially included a total of 1097 patients. After applying a 1:3 propensity score matching, we ultimately included 728 patients, comprising 521 recipients of azvudine and 207 recipients of nirmatrelvir/ritonavir. Among them, 463 patients (88.9%) in the azvudine group and 182 patients (87.9%) in the nirmatrelvir/ritonavir group achieved recovery and discharge, with no significant difference between the two groups (<i>P</i> = 0.816). The median time of improvement was 5.5 days (3.3, 9.0) in the nirmatrelvir/ritonavir group and 5.0 days (4.0, 8.0) in the azvudine group, with no significant difference observed between the two groups (<i>P</i> = 0.732). Furthermore, no significant differences were noted in terms of the time to fever resolution in patients with fever (<i>P</i> = 0.547), the rates of usage of high-flow nasal cannula (<i>P</i> = 0.054), non-invasive mechanical ventilation (<i>P</i> = 0.531), and invasive mechanical ventilation (<i>P</i> = 0.667), the duration of invasive mechanical ventilation usage (<i>P</i> = 0.732), the rate of disease progression (<i>P</i> = 0.602), and hospital length of stay (<i>P</i> = 0.884). Regarding safety outcomes, there was a notable increase in the occurrence of myocardial injury in the nirmatrelvir/ritonavir group (13.5%) compared to the azvudine group (7.3%) (<i>P</i> = 0.012). The two groups did not exhibit differences in the incidence of other adverse events.</p> Conclusion <p>In hospitalized patients with COVID-19, the effectiveness of azvudine and nirmatrelvir/ritonavir was found to be comparable in various aspects, including the improved discharge rate, the improvement time, time to fever resolution, usage rates of high-flow nasal cannula, non-invasive mechanical ventilation, and invasive mechanical ventilation, rate of disease progression, time to discharge, and hospital length of stay. The occurrence of myocardial injury was higher in nirmatrelvir/ritonavir group compared to azvudine group, while no significant differences were observed in other adverse reactions.</p>