Previous preclinical evidence indicates a protective role of quercetin against inflammatory bowel disease (IBD). However, there is no evidence from human populations, resulting in knowledge gaps regarding the role of quercetin in the IBD development. We aimed to prospectively evaluate the associations between dietary quercetin intake and IBD in humans and animal models. We included 187 709 IBD-free participants from the UK Biobank. Dietary information was collected using validated 24-hour dietary recalls and the quercetin intake was estimated based on national nutrient databases. Incident IBD was ascertained inpatient and primary care data. Cox proportional hazard models were used to estimate the multi-variable adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). Experiments were conducted in two chemical-induced (dextran sulfate sodium salt and trinitro-benzene-sulfonic acid) mouse models orally pretreated with quercetin (CAS number: 117-39-5) solution to evaluate the effects of quercetin at physiological levels. After a mean follow-up of 9.7 years, we documented 863 incident IBD. Compared to participants with the lowest quintile intake of quercetin, those in the highest quintiles were associated with a lower risk of IBD (aHR 0.76, 95% CI 0.60-0.95; -trend = 0.004) and ulcerative colitis (aHR 0.69, 95% CI 0.53-0.91; -trend = 0.001), but not Crohn's disease (aHR 0.95, 95% CI 0.62-1.45; -trend = 0.765). Mouse models showed that pretreatment with quercetin could attenuate the chemically induced colitis. Higher quercetin intake was associated with a lower risk of IBD, especially UC. The protective role of quercetin is promising in humans and warrants further investigation into downstream mechanisms.