BACKGROUND & AIMS: Adiposity, type 2 diabetes, alcohol and coffee consumption, and smoking have been examined in relation to diverticular disease in observational studies. We conducted a Mendelian randomization study to assess the causality of these associations. METHODS: Independent genetic instruments associated with the studied exposures at genome-wide significance were obtained from published genome-wide association studies. Summary-level data for the exposure-associated single nucleotide polymorphisms with diverticular disease were available in the FinnGen consortium (10,978 cases and 149,001 noncases) and the UK Biobank study (12,662 cases and 348,532 noncases). RESULTS: Higher genetically predicted body mass index and genetic liability to type 2 diabetes and smoking initiation were associated with an increased risk of diverticular disease in meta-analyses of results from the two studies. The combined odds ratio of diverticular disease was 1.23 (95% confidence interval [CI], 1.14-1.33; P < .001) for a 1-standard deviation (~4.8 kg/m) increase in body mass index, 1.04 (95% CI, 1.01-1.07; P = .007) for a 1-unit increase in log-transformed odds ratio of type 2 diabetes, and 1.21 (95% CI, 1.12-1.30; P < .001) for a 1-standard deviation increase in prevalence of smoking initiation. Coffee consumption was not associated with diverticular disease, whereas the association for alcohol consumption largely differed between the 2 studies. CONCLUSIONS: This study strengthens the causal associations of higher body mass index, type 2 diabetes, and smoking with an increased risk of diverticular disease. Coffee consumption is not associated with diverticular disease. Whether alcohol consumption affects the risk of diverticular disease needs further investigation.