Although pulmonary ground-glass nodules (GGNs) are encountered as common incidental findings, limited evidence exists regarding antibiotic prescriptions in managing GGNs. This study aimed to examine the clinical impact of antibiotics in treating patients presenting with GGNs. This retrospective study was conducted at West China Hospital of Sichuan University, involving 2,609 participants with incidentally detected GGNs between August 10, 2018 and July 22, 2022. Treatments were classified into antibiotic prescription versus no antibiotic prescription. Baseline characteristics and incidences of clinical outcomes (surgical resection, lung cancer diagnosis, beneficial response, and GGN growth) were evaluated. Of the 867 participants finally analyzed (184 antibiotic users; 683 antibiotic non-users), 85.2% were never smokers, and 34.7% presented with respiratory symptoms. The decision to prescribe antibiotics was correlated with the presence of symptoms and larger nodules. After propensity score matching, a higher incidence of surgical resection was observed in antibiotic users versus matched controls (40.8% vs. 29.9%, p = 0.049), whereas there was a trend toward an increased rate of lung cancer diagnosis, which was not statistically significant (32.6% vs. 22.8%, p = 0.054). Significant differences in radiographic response were not found, even among patients with suspected infection. In conclusion, limited beneficial effects of antibiotic use in the management of GGNs were observed, even among patients with suspected infection. These findings do not support empiric antibiotic administration in GGNs and call for efforts to develop outpatient antibiotic stewardship programs.© 2025. The Author(s).