Objective To perform a systematic review and meta-analysis to evaluate the efficacy and safety of prophylactic use of antibiotics in preventing severe acute pancreatitis. Methods Randomized control trials (RCTs) of prophylactic use of antibiotics were identified from PubMed, EMbase, Cochrane Library, Web of Science, CNKI, Wangfang Database, and handly searched related literatures. The retrieval time was from inception to Dec. 2017. All the data would be analysis with the software RevMan 5.3. Results Eventually 16 RCTs of 999 participants were involved, the patients were divided into two groups: the intervention group (prophylactic use of antibiotics, n=501) and the control group (n=498). The result of meta-analysis showed that, the incidence rate of pancreatitis infectious disease and the incidence rate of peripancreatitis infectious were significant lower in the intervention group than the control group, whose OR were amount to 0.68 ［95% CI was (0.50, 0.93), P=0.02］ and 0.63 ［95% CI was (0.45, 0.88), P=0.007］ respectively. Meanwhile, concerning the rate of surgery intervention ［OR=0.79, 95% CI was (0.57, 1.08), P=0.14］ and in mortality rate ［OR=0.81, 95% CI was (0.56, 1.15), P=0.24］, there was no statistically significant. Conclusion Prophylactic antibiotic treatment can do benefit to reduce the incidence rate of pancreatitis infectious and the rate of peripancreatitis infectious disease, but can not reduce mortality in patients with severe acute pancreatitis and had no significant protective effect in patients in reducing the rate of surgery intervention and mortality rate.