Objective To systematically evaluate the efficacy of epinephrine in preventing post⁃endoscopic retrograde cholangiopancreatography pancreatitis (PEP). Methods Randomized controlled trials (RCTs) on epinephrine for preventing PEP from inception to October 10, 2020 were searched in databases including PubMed, Embase, The Cochrane Library, Web of Science, VIP Information Network, China National Knowledge Infrastructure,WanFang Data,and clinical trial registration platforms including ClinicalTrials.gov,WHO International Clinical Trial Registration Platform. Literature was screened independently by two reviewers, data were extracted and the risk of bias of included studies were assessed. The meta-analysis was performed by RevMan 5.3. Results A total of 410 papers were retrieved and 8 RCTs involving 4 208 patients were included. The results of meta-analysis showed that compared with the saline group, the epinephrine could reduce the incidence of PEP (RR=0.29,95%CI:0.16-0.50,P<0.001). There were no significant differences in the therapeutic effect between group epinephrine and group indomethacin (RR=0.17,95%CI:0.02-1.39,P=0.100) or group indomethacin combined with epinephrine and group indomethacin (RR=1.15,95%CI:0.61-2.16,P=0.670). Conclusion Local spraying of epinephrine on the duodenal papilla can reduce the incidence of PEP compared with normal saline. But the epinephrine or combination of indomethacin and epinephrine fails to reveal any benefit over indomethacin alone in preventing PEP.