Objective: The paper analyzes the impact of DRG payment on hospitalization costs of cross-region patients within the province, in order to provide empirical evidence for reforming payment methods of cross-region healthcare. Methods: The data of cross-region inpatients in a grade-A tertiary hospital in Shandong Province from 2022 to 2024 was collected. Descriptive statistical analysis, nonparametric rank sum test and interrupted time series model were used to analyze the changes of hospitalization costs of cross-region patients within the province before and after the implementation of DRG payment, and explore the synergy effect between DRG payment and the policy of centralized drug procurement in controlling drug costs. Results: After the implementation of the DRG payment reform, all the average hospitalization costs, the average personal burden costs and the average pooling fund expenses of the cross-region patients within the province have decreased, and the hospitalization cost structure has been optimized, but the long-term trend change is not obvious. Meanwhile, DRG payment and centralized drug procurement policies have synergy effect on reducing drug costs, with a cumulative decrease of 25.51% in the average drug costs. Conclusion: The reform of DRG payment for cross-region healthcare has achieved encouraging results, we need to establish a more scientific and rational payment standard, deeply investigate and optimize the classification and pricing mechanism of DRG basic disease groups, establish a multi-stakeholder consultation and communication mechanism and strengthen policy synergy effect to further promote the reform of medical insurance payment for cross-site healthcare.