Prior observational studies have reported the potential protective effect of omega-3 fatty acids on the prognosis of acute pancreatitis. However, the causal impact of omega-3 fatty acids on acute pancreatitis is unclear. We aimed to investigate further the association of omega-3 fatty acids with acute pancreatitis. We performed a meta-analysis and Mendelian randomization (MR) to explore the association between omega-3 fatty acids and the prognosis of acute pancreatitis from clinical observation and genetics perspectives, respectively. 9 randomized controlled trials were included in this study. The result meta-analysis showed that complementary therapy of omega-3 fatty acids significantly decreased mortality (RR: 0.30; 95% CI 0.14 to 0.65, P＜0.05) and infectious complications in acute pancreatitis (RR: 0.45; 95% CI 0.27 to 0.77, P＜0.05). Compared to the control groups, the hospital stays (MD: -1.02; 95% CI -1.85 to -0.20, P＜0.05) in acute pancreatitis patients with omega-3 fatty acids treatment were statistically reduced. However, the ICU stay (MD: -0.49; 95% CI -1.29 to -0.31, P＞0.05) between control groups and acute pancreatitis patients with omega-3 fatty acids treatment was insignificant. Utilizing genetic susceptibility analysis in the Mendelian randomization (MR) approach, the MR showed omega-3 fatty acids have a significant causal effect on the acute pancreatitis risk (OR, 0.887; 95% CI, 0.797-0.986, P = 0.027, fixed-effect; OR, 0.887; 95% CI, 0.792-0.993, P = 0.037, random-effect). Omega-3 fatty acids complementary therapy may improve the prognosis of acute pancreatitis. Furthermore, genetically predicted serum levels of omega-3 fatty acids can significantly lower acute pancreatitis risk.