<p>Gastrointestinal (GI) cancers are among the most deadly cancers globally, with smoking being a significant risk factor. This study analyzes the burden of smoking-related GI cancers from 1990 to 2021 using data from the Global Burden of Disease (GBD) Study 2021 and projects trends to 2050. Estimates of smoking-related GI cancers were obtained from the Global Health Data Exchange (GHDx). These estimates represent deaths specifically attributable to smoking, derived from a multi-step modelling process combining smoking prevalence, relative risks, and total cancer mortality across 204 countries and territories, and are substantially lower than total cancer deaths. The burden was assessed using the age-standardized death rates (ASDRs) and its estimated annual percentage changes (EAPCs) across global, regional, and socioeconomic levels. Predictive analysis was conducted using a Bayesian Age-Period-Cohort (BAPC) model. In 2021, among smoking-related GI cancers, esophageal cancer had the highest global number of deaths (205,463), followed by stomach cancer (107,926), pancreatic cancer (72,170), liver cancer (53,054), and colon/rectum cancer (47,613). ASDRs and deaths were higher in males than females, peaking after age 65. From 1990 to 2021, ASDRs decreased for all smoking-related GI cancers, with the largest declines in stomach cancer (EAPC: −&#xa0;2.63%) and esophageal cancer (EAPC: -1.38%). However, geographical and socioeconomic variations were evident. By 2050, deaths from various smoking-related GI cancers are projected to rise, with the ASDRs increasing for esophageal cancer but decreasing for stomach, colon/rectum, liver, and pancreatic cancers. Although the ASDRs of smoking-related GI cancers have declined, disparities persist across age, sex, geographical and development levels. Continued efforts to reduce smoking prevalence are essential to prevent further increases in GI cancer burden and improve global health outcomes.</p>