IntroductionThere is still a lack of clinical evidence comprehensively evaluating the effectiveness of antiviral treatments for COVID‐19 hospitalized patients.MethodsA retrospective cohort study was conducted at Beijing You'An Hospital, focusing on patients treated with nirmatrelvir/ritonavir or azvudine. The study employed a tripartite analysis—viral dynamics, survival curve analysis, and AI‐based radiological analysis of pulmonary CT images—aiming to assess the severity of pneumonia.ResultsOf 370 patients treated with either nirmatrelvir/ritonavir or azvudine as monotherapy, those in the nirmatrelvir/ritonavir group experienced faster viral clearance than those treated with azvudine (5.4 days vs. 8.4 days, p < 0.001). No significant differences were observed in the survival curves between the two drug groups. AI‐based radiological analysis revealed that patients in the nirmatrelvir group had more severe pneumonia conditions (infection ratio is 11.1 vs. 5.35, p = 0.007). Patients with an infection ratio higher than 9.2 had nearly three times the mortality rate compared to those with an infection ratio lower than 9.2.ConclusionsOur study suggests that in real‐world studies regarding hospitalized patients with COVID‐19 pneumonia, the antiviral effect of nirmatrelvir/ritonavir is significantly superior to azvudine, but the choice of antiviral agents is not necessarily linked to clinical outcomes; the severity of pneumonia at admission is the most important factor to determine prognosis. Additionally, our findings indicate that pulmonary AI imaging analysis can be a powerful tool for predicting patient prognosis and guiding clinical decision‐making.