Diagnosing lung cancer from indeterminate pulmonary nodules (IPLs) remains challenging. In this multi-institutional study involving 2032 participants with IPLs, we integrate the clinical, radiomic with circulating cell-free DNA fragmentomic features in 5-methylcytosine (5mC)-enriched regions to establish a multiomics model (clinic-RadmC) for predicting the malignancy risk of IPLs. The clinic-RadmC yields an area-under-the-curve (AUC) of 0.923 on the external test set, outperforming the single-omics models, and models that only combine clinical features with radiomic, or fragmentomic features in 5mC-enriched regions (p < 0.050 for all). The superiority of the clinic-RadmC maintains well even after adjusting for clinic-radiological variables. Furthermore, the clinic-RadmC-guided strategy could reduce the unnecessary invasive procedures for benign IPLs by 10.9% ~ 35%, and avoid the delayed treatment for lung cancer by 3.1% ~ 38.8%. In summary, our study indicates that the clinic-RadmC provides a more effective and noninvasive tool for optimizing lung cancer diagnoses, thus facilitating the precision interventions.© 2024. The Author(s).