Background: Human adenovirus (HAdV) commonly affects children hospitalized with any form of respiratory infection (RI). Severe HAdV infection leads to one of the most serious types of infantile RI, with rapidly progressive illness and a poor prognosis. Objectives: This study investigated the relationship between aspartate aminotransferase (AST) levels and the severity of HAdV RI in children. Methods: We collected clinical data from 665 cases of HAdV RI in children hospitalized at the pediatric ward of Changde First People's Hospital between January and December 2019. We analyzed the relationship between AST levels and disease severity. Results: Of the 665 HAdV-positive cases, 89.8% were < 6 years of age. Among them, upper RI was diagnosed in 18.8% of cases, bronchiolitis in 4.8%, and mild pneumonia in 48.1%. Severe pneumonia was observed in 28.2% of cases. The 665 patients in the cohort were divided into a mild group (n = 477 cases, 71.73%) and a severe group (n = 188 cases, 28.27%). Univariate analysis showed that children with severe HAdV RI had a lower age of onset and lower hemoglobin and serum albumin levels while having higher platelet counts, lactic acid dehydrogenase, creatine kinase, creatine kinase isoenzyme, alanine aminotransferase, and AST levels compared to those with mild infections (P < 0.05). Multivariate analysis revealed that these factors were related to disease severity (P < 0.05). The ROC curve analysis indicated that the area under the AST curve was 0.782. When the intercept value was 52.5 U/L, the sensitivity was 60.6%, and the specificity was 83.4%. Conclusions: Serum AST levels can serve as a predictor of adenoviral RI severity in children.