GI cancers pose an increasing global health burden, with their impact on the working-age population (WAP) aged 15-64 years remaining largely unexplored despite the crucial role of this group in societal and economic well-being.To assess trends and cross-country inequality in the global burden of six GI cancers from 1990 to 2021 among individuals in the WAP.The 2021 Global Burden of Disease study dataset was used to obtain estimates of GI cancer incidence and 95% uncertainty intervals, including the number of cases, crude incidence rate and age-standardised incidence rate (ASIR). WAP GI cancer epidemiology was assessed at the national, regional and global levels, evaluating trends from 1990 to 2021 from overall, local and Sociodemographic Index (SDI) perspectives and using standard health equity methods to quantify cross-country inequality.Colorectal cancer exhibited the greatest burden of GI cancer among the WAP in 2021. From 1990 to 2021, the number of GI cancer cases rose by 51.9%, although the ASIR declined by 23.4%. These rates exhibit geographic variation, with the most cases and the highest ASIR in China and Mongolia, respectively. Incidence was disproportionately concentrated in higher SDI countries, and worsening inequality was evident over time.While the ASIR of GI cancer is trending downwards among the WAP, high incidence rates, regional variability and an unequal burden of disease emphasise the need for flexible, targeted medical interventions to support policymaking and medical resource allocation.© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ Group.