BACKGROUND: Sequelae and complications have become a significant concern in the post-pandemic era of Coronavirus disease 2019 (COVID-19). However, it remains unclear whether there is a direct causal relationship between COVID-19 or vaccination and digestive diseases, as existing evidence is ambiguous and controversial. In this study, we investigated the associations between multiple COVID-19 infection phenotypes, vaccination, and 20 common digestive diseases, and explored their causal relationships through extensive Mendelian randomization (MR) analysis. METHODS: For individuals of European descent, we conducted an extensive two-sample Mendelian randomization (MR) analysis using genome-wide association study (GWAS) data. Six COVID-19 infection (six phenotypes) GWAS datasets and two vaccination (from the UK and Finland) GWAS datasets were used as exposure factors; 20 common digestive diseases were treated as outcome factors, with each disease having two or more GWAS datasets, mostly sourced from the UK Biobank and FinnGene platforms. Single nucleotide polymorphisms (SNPs) associated with the exposures were used as instrumental variables (IVs) to estimate the causal relationship between COVID-19, vaccination, and the 20 digestive diseases. Meta-analysis was conducted to assess the combined causal effect from multiple MR results. RESULTS: MR analysis revealed a causal relationship between COVID-19 and duodenal ulcer (P = 4.98E-03, OR = 1.00, 95% CI: 1.00-1.00). Additionally, COVID-19 hospitalization was associated with viral hepatitis (P = 4.94E-02, OR = 1.10, 95% CI: 1.00-1.21), cirrhosis (P = 1.72E-02, OR = 0.91, 95% CI: 0.85-0.98), and chronic pancreatitis (P = 1.48E-02, OR = 0.91, 95% CI: 0.84-0.98). Severe COVID-19 infection was linked to viral hepatitis (P = 3.57E-02, OR = 1.00, 95% CI: 1.00-1.00), cholelithiasis (P = 3.50E-02, OR = 1.00, 95% CI: 1.00-1.00), and Crohn's disease (P = 4.15E-02, OR = 0.96, 95% CI: 0.93-1.00). Meta-analysis further supported a causal link between COVID-19 and duodenal ulcer (P = 4.97E-03, OR = 1.00, 95% CI: 1.00-1.00), gastroesophageal reflux disease (P = 3.38E-02, OR = 1.04, 95% CI: 1.00-1.07), and chronic pancreatitis (P = 2.67E-03, OR = 0.92, 95% CI: 0.87-0.97). COVID-19 vaccination (Finland) was associated with an increased risk of gastroesophageal reflux disease (P = 3.38E-02, OR = 1.12, 95% CI: 1.01-1.24). After applying the Benjamini-Hochberg correction, no significant differences were observed in the meta-analysis results. CONCLUSIONS: This extensive MR study found no strong causal relationship between COVID-19 infection, vaccination, and 20 common digestive diseases based on genetic data. These results help clarify the longstanding uncertainty surrounding the potential causal links between COVID-19-related factors and digestive diseases. Our findings suggest that genetic variants associated with COVID-19 infection and vaccination do not significantly influence the risk of these diseases, which could inform clinical treatment strategies and public health guidelines.