Background <p>The dietary index for gut microbiota (DI-GM) is a newly proposed index that evaluates dietary intake patterns associated with gut microbial health. Limited studies have examined whether DI-GM influences gastrointestinal (GI) cancer risk. We aimed to investigate the association between DI-GM and GI cancer risk and evaluate its combined effect with genetic risk.</p> Methods <p>We included 178,148 UK Biobank participants who completed at least one 24-hour dietary recall. DI-GM was constructed from 13 dietary components known to influence gut microbial health and was divided into three groups. The GI cancer polygenic risk score was calculated from 205 significant single-nucleotide polymorphisms related to esophageal cancer (EC), gastric cancer (GC), and colorectal cancer (CRC). Cox proportional hazards models with hazard ratios (HRs) and 95% confidence intervals (CIs) were used to estimate the associations between DI-GM, genetic risk, and GI cancer.</p> Results <p>During a median follow-up of 13.47 years, 2,682 participants developed GI cancer. In fully adjusted models, higher DI-GM was associated with a lower GI cancer risk (HR for GI cancer: 0.83; 95% CI: 0.75–0.92; HR for EC: 0.62, 95% CI: 0.45–0.86; HR for GC: 0.99, 95% CI: 0.71–1.39; HR for CRC: 0.84, 95% CI: 0.75–0.95), compared with participants in the lowest DI-GM category. In joint analysis, individuals with higher DI-GM and lower genetic risk had lower GI cancer risk, with HRs (95% CI) of 0.28 (0.21, 0.36), 0.50 (0.42, 0.58) for low and intermediate genetic risk, respectively, compared with those with low DI-GM and high genetic risk. And a significant interaction between DI-GM and genetic risk was observed.</p> Conclusion <p>Higher DI-GM was associated with a lower risk of GI cancer including EC and CRC. These findings highlight the importance of considering a gut microbiota-friendly diet and genetic risk in GI cancer prevention.</p>