Background: Concerns about rising health care cost and quality of care has been a major health issue worldwide. Gastrointestinal (GI) cancer accounts for one-quarter of the global cancer incidence. However, there are limited evidence, which demonstrates the differences in clinical outcome and economic burden of GI cancer when comparing between health care setting of developed and developing countries. Methods: Two data sources were analyzed: (i) The 2020 U.S. National Inpatient Sample (NIS) involving patients that were primarily discharged with gastroenterological cancer, and (ii) data at tertiary care center in Thailand used for this comparative study, with similar period and conditions. Participants were identified using relevant ICD-10 CM codes. Adjusted odds ratios (aORs) for specified outcomes were calculated through multivariate logistic and linear regression analyses. Participants are divided into those who experienced mortality and those who survived. We report crude mortality rates and expenditure outcomes. Statistical significance was established at a p-value of 0.05. Results: We identified 9,299 Thai records and estimated 216,859 US records with a primary diagnosis of GI cancer at discharge. Of these, 2.15% (200/9,299) of the Thai records and 3.82% (8,285/216,859) of the US records died. In a multivariate analysis, death during hospitalization is associated with higher length of stay (Thai: b = 18.10, 95% CI (16.71, 19.49), p < 0.001), (US: b = 3.38, 95% CI 3.38 (2.14, 4.63), p < 0.001) and higher hospitalization charges (Thai: b = 155,530.02 THB, 95% CI (141,805.10, 169,254.80), p < 0.001), (US: b = 46,882.44 USD, 95% CI (31,629.51, 62,135.37), p <0.001). Subpopulation analysis revealed similar significant results. We observed higher increased length of stay in Thailand, whereas higher crude mortality rate and hospitalization charges was observed in the United States. Conclusions: In both Thailand and United States, mortality in patient with GI cancer is associated with increase in length of stay and higher hospitalization expenses. However, the magnitude of difference in each outcome differs between two countries. Future studies investigating health care costs, cultural role and clinical outcomes may provide insights for cost-reduction strategies, while maintaining or improving the current standard of care in this population group.