Background and AimThis study investigates temporal trends in gastrointestinal cancer‐related mortality in the United States between 1999 and 2020, focusing on differences by sex, age, and race.MethodsWe investigated the Centers for Disease Control and Prevention Wide‐Ranging Online Data for Epidemiologic Research multiple causes of death database (Years 1999–2020) for gastrointestinal cancer‐related mortality with a focus on the underlying cause of death.ResultsA total of 3 115 243 gastrointestinal cancer‐related deaths occurred from 1999 to 2020. The overall age‐adjusted mortality rate decreased from 46.7 per 100 000 in 1999 to 38.4 per 100 000 in 2020. The average annual percent change (AAPC) for the study period was −0.9% (95% CI: −1.0%, −0.9%, P < 0.001), with no significant difference in AAPC between the sexes but some difference between races and related to individual cancers. African Americans and Asian Americans, and Pacific Islanders experienced a greater decrease in mortality compared with Whites. Mortality rates for American Indian and Alaskan Native populations also decreased significantly from 1999 to 2020 (P < 0.001). There were significant declines in esophageal, stomach, colon, rectal, and gallbladder cancer‐related mortality but increases in the small bowel, anal, pancreatic, and hepatic cancer‐related mortality (P < 0.001), with variation across different sexes and racial groups.ConclusionWhile overall gastrointestinal cancer‐related mortality declined significantly in the United States from 1999 to 2020, mortality from some cancers increased. Furthermore, differences between sexes and racial groups underscore crucial differences in gastrointestinal cancer mortality, highlighting areas for future research.