Objective To explore the impact of healthcare-associated infection (HAI) on the economic burden of lung cancer patients and specific impact pathways under the background of diagnosis-related group (DRG) payment. Methods Data from the home page of medical record and HAI system of lung cancer patients in a hospital from Ja-nuary 2023 to June 2024 were collected retrospectively. Based on the occurrence of HAI, patients were grouped and matched according to propensity score. Correlation among various factors in patient’s hospitalization expense was analyzed using grey correlation method. The impact of HAI on hospitalization expense was explored by multivariate linear regression and threshold regression models. The mediation effect of length of hospital stay was explored by mediation effect model. Results The incidence of HAI in 2 808 lung cancer patients was 5.91%. After matching, data from 126 pairs of patients were included in the analysis, with the respiratory system being the major infection site (60.32%). Patients with catheter-related bloodstream infection had the highest hospitalization expense (142 582.01 Yuan). In the HAI group, the proportion of medicine expense was the highest (27.89%), and diagnostic expenses had the highest correlation with hospitalization expenses (0.946). Multivariate linear regression results showed that HAI could result in an increase in the average hospitalization expense of lung cancer patients by 47 203.27 Yuan and an extension of the length of hospital stay by 17.89 days. The length of hospital stay played a partial mediating role in the impact of HAI on hospitalization expense, with the mediating effect accounting for 53.30%. The threshold effect model showed that HAI had a significant promoting effect on the expense when the length of hospital stay exceeded 19 days, and the longer the length of hospitalization, the greater the impact. Conclusion HAI can significantly increase the economic burden on patients by prolonging the length of hospital stay. It is necessary to control the expenditure of medication and diagnostic expenses rationally, optimize the hospitalization expense structure of infected patients, reflect the value of knowledge and technical labor of healthcare workers, standardize medical procedures, as well as strengthen HAI prevention and control.