Background <p>Gastric acid suppressants, including proton pump inhibitors (PPIs) and histamine H2-receptor antagonists, are widely used globally. Their long-term safety remains a concern, particularly regarding gastrointestinal cancer risks.</p> Aims <p>To assess population-level associations between gastric acid suppressant use and the incidence of major gastrointestinal cancers, adjusting for potential confounders.</p> Methods <p>This ecological panel study analyzed country-year data from 24 nations (1990–2020). Consumption of acid suppressants (ATC A02B, DDD/1000/day) was obtained from OECD Health Statistics. Age-standardized cancer incidence rates (colorectal, liver, pancreatic, esophageal) were sourced from the GBD 2019 dataset. Multivariable linear mixed-effects models were adjusted for dietary risks, BMI, tobacco, alcohol, antibiotics, NSAIDs, and GDP per capita.</p> Results <p>Higher acid suppressant use was significantly associated with increased liver cancer (<i>β</i> = 0.0086; 95% CI 0.0019 to 0.0154; <i>p</i> = 0.0136) and pancreatic cancer (<i>β</i> = 0.0148; 95% CI 0.0068 to 0.0227; <i>p</i> = 0.0004) incidence. No significant associations were found for colorectal or esophageal cancers. Model fit was strongest for liver and pancreatic outcomes.</p> Conclusions <p>While causal inference cannot be drawn from ecological data, the findings suggest a population-level association between gastric acid suppressant consumption and increased liver and pancreatic cancer incidence. These results support the need for cautious prescribing and further research using individual-level data.</p>