Acute pancreatitis (AP) and chronic pancreatitis (CP) have high incidences and poor prognoses. The early screening of at-risk populations still awaits further study. The limitation was mainly based on observational studies, with limited sample size and the presence of confounding factors. This study used a 2-sample Mendelian randomization (MR) analysis based on publicly available data from genome-wide association studies to reveal the causal effect of gut microbiota and metabolites on pancreatitis.This study collected summary statistics on gut microbiota, metabolites, AP, and CP. A 2-sample MR analysis was performed using MR-Egger, inverse variance-weighted, MR Pleiotropy RESidual Sum and Outlier, maximum likelihood, and weighted median.The 2-sample MR showed that only Eubacterium coprostanoligenes was an independent protective factor for AP among all gut microbiota, and the other microbiota were not significant for pancreatitis. Unsaturated fatty acids in metabolites are protective factors for both AP (odds ratio [OR], 0.730; 95% CI, 0.593-0.899; P = .003) and CP (OR, 0.660; 95% CI, 0.457-0.916; P = .013). Furthermore, carnitine was a protective factor CP, and glucose was an independent risk factor for CP.This study provides potential evidence of the causal role of gut microbiota and metabolites on pancreatitis, which may be conducive for designing microbiome and metabolite interventions on AP or CP in the future.Copyright © 2024. Published by Elsevier Inc.