Objective To analyze the influencing factors for over⁃expenditure of cases in clinical departments' diagnosis related groups (DRG) settlement, and to provide ideas for the departments' delicacy management. Methods Medical insurance settlement information, medical record information, and expense information of 1495 cases with DRG settlement in Department of Cardiovascular Medicine from a class Ⅲ comprehensive hospital in 2022 were selected. The univariate analysis and multivariate Logistic regression model were used to analyze the influencing factors for over⁃expenditure of cases with DRG settlement. Results The results of univariate analysis revealed that there were statistically significant differences in age, length of hospital stays, medical insurance type, case type, disease severity, type of therapeutic operation, relative weight (RW), and proportions of drugs, consumptive materials, examination and tests, and medical service between the balance case group and the over⁃expenditure group (P<0.05). The results of multivariate Logistic regression analysis revealed that length of hospital stays≥5 days, medical insurance for urban and rural residents, low or high magnification cases, high drugs proportion, and high proportion of consumptive materials were the risk factors for over⁃expenditure of cases with DRG settlement (P<0.05), whereas non⁃operating room operation, RW≥2 were the protective factors for over⁃expenditure of cases with DRG settlement (P<0.05). Conclusion Clinical departments can actively adapt to medical insurance rules, implement clinical path management, strengthen medical expenditure control, take into account the high⁃quality development of disciplines and other aspects of continuous improvement, promote DRG delicacy management, and help the sustainable development of hospitals.