Objective: This study aimed to develop and validate an interpretable machine learning model for early prediction of carbapenem-resistant Klebsiella pneumoniae (CRKP) infection using routine peripheral blood indicators, providing a rapid risk assessment tool before antimicrobial susceptibility results. Methods: A retrospective study was conducted on 285 patients with culture-confirmed Klebsiella pneumoniae infection (242 carbapenem-susceptible Klebsiella pneumoniae (CSKP), 43 CRKP), with all isolates obtained from sputum specimens, from June 2024 to June 2025. Given the significant class imbalance between the CSKP (n = 242) and CRKP (n = 43) groups, key features were screened by LASSO regression and Boruta algorithm. Six machine learning models were constructed, with synthetic minority oversampling technique (SMOTE) for class imbalance processing and stratified 5-fold cross-validation for optimization. Model performance was evaluated by area under the curve (AUC), accuracy, calibration curve, decision curve analysis (DCA), and interpreted by SHapley Additive exPlanations (SHAP). Results: Seven core predictors (HGB, LYMPH_p, NEUT_p, MONO, BASO, PCT, AISI) were identified. The random forest model achieved the best performance, with an AUC of 0.863 (95% CI: 0.672– 0.980), accuracy of 0.821, sensitivity of 0.750 (95% CI: 0.571– 1.000), specificity of 0.834 (95% CI: 0.643– 0.841), and Brier score of 0.077. DCA showed clear net benefit in the threshold probability range of 0.1– 0.8. SHAP analysis confirmed aggregate index of systemic inflammation (AISI) as the most important predictive factor. Conclusion: The interpretable prediction model based on routine peripheral blood indicators demonstrated good discrimination, calibration, and clinical utility in this single-center retrospective study. It has the potential to assist early risk stratification of CRKP infection and support clinical decision-making. External multicenter prospective validation is warranted before clinical implementation.