Backgrounds and Objectives Childhood obesity and respiratory tract infections (RTIs) are 2 major global public health issues that frequently co-occur and are closely interrelated. Early detection of children with prior RTIs who are at high obesity risk is crucial for targeted interventions. This study integrates interpretable machine learning (ML) models and a deep learning network to develop an obesity risk prediction model in a large pediatric cohort.Methods Cross-sectional data from 6509 children and adolescents aged 3-12 years with prior RTIs in Beijing and Tangshan were fed to 12 ML models to predict childhood obesity (versus children with normal weight). Bayesian optimization was applied to fine-tune model hyperparameters. Prediction performance was assessed using 8 metrics. Key predictive features were identified by SHapley Additive exPlanations (SHAP). The validity of the optimal ML model was verified by the sequential neural network model.Results Of 12 ML models, LightGBM achieved the optimal performance (accuracy: 0.8844, area under the curve [AUC]: 0.9491). SHAP analysis identified 20 key predictors, including child age, paternal body mass index (BMI), maternal BMI, birth length, birthweight, gestational age, eating speed, complementary feeding initiation age, screen time, breastfeeding duration, bedtime, maternal age, nighttime sleep, outdoor activity, dental caries, sedentary time, food allergies, family history of diabetes, and sex. The deep learning sequence network model further validated the predictive value of these features (accuracy: 0.8023, AUC: 0.8117), and the SHAP-driven feature importance rankings were in close line with LightGBM.Conclusions Our LightGBM-based model enables effective prediction of obesity risk in children aged 3-12 years with prior RTIs, and the key features identified can inform early screening and facilitate personalized interventions.