Abstract Objectives To develop and validate a preoperative CT-based nomogram combined with radiomic and clinical–radiological signatures to distinguish preinvasive lesions from pulmonary invasive lesions. Methods This was a retrospective, diagnostic study conducted from August 1, 2018, to May 1, 2020, at three centers. Patients with a solitary pulmonary nodule were enrolled in the GDPH center and were divided into two groups (7:3) randomly: development (n = 149) and internal validation (n = 54). The SYSMH center and the ZSLC Center formed an external validation cohort of 170 patients. The least absolute shrinkage and selection operator (LASSO) algorithm and logistic regression analysis were used to feature signatures and transform them into models. Results The study comprised 373 individuals from three independent centers (female: 225/373, 60.3%; median [IQR] age, 57.0 [48.0–65.0] years). The AUCs for the combined radiomic signature selected from the nodular area and the perinodular area were 0.93, 0.91, and 0.90 in the three cohorts. The nomogram combining the clinical and combined radiomic signatures could accurately predict interstitial invasion in patients with a solitary pulmonary nodule (AUC, 0.94, 0.90, 0.92) in the three cohorts, respectively. The radiomic nomogram outperformed any clinical or radiomic signature in terms of clinical predictive abilities, according to a decision curve analysis and the Akaike information criteria. Conclusions This study demonstrated that a nomogram constructed by identified clinical–radiological signatures and combined radiomic signatures has the potential to precisely predict pathology invasiveness. Key Points • The radiomic signature from the perinodular area has the potential to predict pathology invasiveness of the solitary pulmonary nodule. • The new radiomic nomogram was useful in clinical decision-making associated with personalized surgical intervention and therapeutic regimen selection in patients with early-stage non-small-cell lung cancer.