Objective To explore the application of disease diagnosis-related group (DRG) payment method in healthcare-associated infection (HAI) monitoring and its impact on medical resource consumption. Methods The basic information and settlement list information of hospitalized patients in a hospital in Liupanshui City from 2020 to 2023 were analyzed retrospectively. DRG grouping was carried out based on CN-DRG Grouping Scheme (2023), research objects in the same DRG group were divided into HAI group and non-HAI group, and case mix index (CMI) was used to correct the cases incidence rate of HAI. Difference in indexes, such as time consumption index, expense consumption index, length of hospital stay, total hospitalization expense, and each detailed expense between HAI group and non-HAI group were compared. Results A total of 143 652 cases were enrolled, the median length of hospital stay in patients in HAI group prolonged by 13 days compared with that of non-HAI patients within the same DRG, the median total hospitalization expense increased by 23 800-28 300 Yuan (both P<0.05). After the adjustment of CMI value in 2023, the case incidence rates of HAI in the department of neurosurgery intensive care unit and the department of critical care medicine declined, with the largest decline in the neurosurgery intensive care unit (15.00%). In the internal medicine DRG, surgical DRG, and procedural DRG, the time consumption index and expense consumption index of HAI group were both higher than those of non-HAI group (both P<0.05). The top 5 DRGs with the highest HAI case incidence rates were AH29 (invasive ventilator support ≥96 hours, 23.05%), GB39 (major surgery of small intestine and large intestine ［including rectum］, 12.00%), ZJ11 (other surgical procedures related to multiple injuries, with serious comorbidity or complications, 8.06%), IE39 (lower limb bone surgery except femur, 3.64%), ES31 (respiratory system infection/inflammation, with serious comorbidity or complications, 0.70%). For DRGs AH29, ES31 and RN25 (targeted therapy and immunotherapy for malignant and proliferative diseases, without serious comorbidity or complications), patients in HAI group had longer hospitalization days, higher total hospitalization expense, and each detailed expense than those of non-HAI group (all P<0.05). Bloodstream infection, skin and soft tissue infection, and surgical site infection had significant impact on the time consumption index; bloodstream infection and urinary tract infection had significant impact on the expense consumption index. Conclusion Under the DRG payment method, HAI significantly increases the consumption of medical resources. Adjusting CMI values can improve the accuracy of assessing the level of infection prevention and control in departments. It is speculated that implementing targeted prevention and control for patients in high-risk infection DRGs and high consumption infection sites can effectively reduce resource waste and promote the synergistic improvement of medical quality and economic benefits under the DRG payment system.