ABSTRACT Background Since the end of 2022, Azvudine was widely used to treat hospitalized novel coronavirus disease 2019 (COVID-19) patients in China. However, data on the clinical effectiveness of Azvudine against severe outcomes and post-COVID-19-conditions (PCC) among patients infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variants was limited. This study evaluates the effectiveness of Azvudine in hospitalized COVID-19 patients during a SARS-CoV-2 Omicron BA.5 dominance period. Methods From 1 November 2022 to 1 July 2023, we conducted a single-center retrospective cohort study based on hospitalized COVID-19 patients from a tertiary hospital in Shihezi, China, recruiting laboratory-confirmed hospitalized patients with SARS-CoV-2 infection. Patients treated with Azvudine and usual care were propensity-score matched (PSM) at a 1:1 ratio to a control group in which patients undergone usual care only, with matching based on covariates such as sex, age, ethnicity, number of preexisting conditions, antibiotic use upon admission, and complete blood cell count. The primary outcomes were all-cause death and PCC at short-term (60 days) post discharge. The secondary outcomes included the initiation of invasive mechanical ventilation and PCC at long-term post discharge (120 days). Cox proportional hazards (PH) regression models were employed to estimate the hazard ratios (HR) for both all-cause death and invasive mechanical ventilation, and logistic regression models were used to estimate the odds ratios (OR) for short-term and long-term PCC. Subgroup analyses were performed based on the matched covariates. Results A total of 2,639 hospitalized patients diagnosed with COVID-19 were initially identified, and 2,069 patients were screened following the exclusion criteria. After matching, 297 Azvudine recipients and 297 matched controls were eligible for analyses. The incidence rate of all-cause death was lower in the Azvudine group than in the control group (0.007 per person, 95% confidence interval [CI]: 0.001, 0.024 vs 0.128, 95% CI: 0.092, 0.171), and the use of Azvudine was associated with a significant lower risk of death and the use of Azvudine was associated with a reduced risk of death (HR: 0.049, 95% CI: 0.012, 0.205). Subgroup analyses indicated a significant effectiveness of Azvudine against the risk of all-cause death among men, age over 65, patients without the preexisting conditions, and patients with antibiotics dispensed at admission. Statistical difference were not observed between Azvudine group and control group in the invasive mechanical ventilation and short-term and long-term PCC. Conclusions The present findings indicate that receipt of Azvudine was associated with lower risk of all-cause death among hospitalized patients with Omicron BA.5 infection a in real-world setting. Further research is urgently needed to validate the effectiveness of Azvudine on the PCC.