Introduction <p>Gastrointestinal (GI) cancers account for over a quarter of all cancer-related deaths in the United States; however, the latest trends in their prevalence remain unclear.</p> Methods <p>Data on GI cancers were obtained from the Global Burden of Disease Study 2021. Age-standardized incidence rates (ASIR) and age-standardized mortality rates (ASMR) were estimated across various states, sexes, ages, and risk factors, and annual percentage changes were calculated.</p> Results <p>From 2000 to 2021, liver cancer exhibited the greatest increase in both the ASIR and the ASMR, followed by pancreatic cancer. In contrast, stomach cancer showed the greatest decline, followed by colorectal cancer, esophageal cancer, and biliary tract cancer. Most GI cancers predominantly affect men and tend toward a younger age of onset. Geographic disparities exist in the burden of GI cancers and their risk factors. For esophageal, stomach, and colorectal cancers, mortality rates linked to diet and smoking decreased, whereas alcohol-related mortality increased in several states, especially West Virginia. Hepatitis C remains the leading cause of liver cancer, with intravenous drug use as the primary risk factor. Non-alcoholic steatohepatitis (NASH) is the fastest-growing cause of liver cancer, followed by excessive alcohol use. Mortality rates for pancreatic cancer due to high body-mass index and high fasting plasma glucose have increased across states and age groups.</p> Discussion <p>The epidemiological trends of GI cancers in the U.S. have shifted substantially. States need to implement targeted policies that address specific populations and risk factors for each cancer type.</p>