Objective To explore the distribution of healthcare-associated infection (HAI) and direct economic burden in neurosurgical patients based on disease diagnosis-related grouping (DRG), providing data support for infection prevention and control. Methods Clinical data of neurosurgical patients in a hospital from January to December 2023 were retrospectively investigated, the average length of hospital stay and average hospitalization expense of HAI and non-HAI groups of the subgroups of DRG were analyzed. Results A total of 102 cases of HAI occurred among 2 180 neurosurgical patients, with HAI incidence being 4.68%. The main infection sites were lower respiratory tract and organ space, accounting for 53.92% and 25.49% respectively. HAI patients distributed in 16 DRG subgroups, out of which AH19 subgroup (invasive ventilator support ≥96 hours or extracorporeal membrane oxygenation ［ECMO］ or total artificial heart transplantation) had the highest incidence (58.82%), followed by BC19 subgroup (intracranial vascular surgery accompanied with hemorrhage diagnosis) (17.65%) and BB2A subgroup (craniotomy other than trauma, with severe or general complications and comorbidities)(12.81%). There was no statistically significant difference in resource consumption between HAI group and control group of AH19 group (all P>0.05). HAI in BB2A group increased the average length of hospital stay and average hospitalization expense by 5.00 days and 34 600 Yuan, respectively. HAI in BC19 group increased the average length of hospital stay and ave-rage hospitalization expense by 8.50 days and 42 800 Yuan, respectively. Lower respiratory tract infection had a significant impact on resource consumption, while organ space infection only increased length of hospital stay of patients. Conclusion Analysis of incidence of HAI and resource consumption of major infection sites based on DRG can clarify the focus of infection prevention and control, formulate targeted intervention measures, control medical expense and improve the quality of medical services.