Acute pancreatitis (AP) is a common but often self-limiting disease in the majority of patients. However, in the minority, who may progress to moderately severe or severe AP, high mortality risk has been reported. Infected pancreatitis necrosis (IPN) in necrotising pancreatitis has been shown to result in more than twice the mortality rate compared with in sterile pancreatic necrosis. This raises the question on whether prophylactic antibiotics (PABs) should be given in subgroups of AP to prevent superimposed infection to improve survival outcomes. Despite numerous randomised controlled trials (RCTs), meta-analyses, and guidelines on the management of AP, there is a lack of strong evidence to suggest the use of PABs in AP. Additionally, use of PABs is associated with antimicrobial resistance. Considerable heterogeneity exists and limits the interpretation of results-subgroup of AP benefitting from PAB use, choice/class of PAB, and timing of administration from symptom onset and duration of PAB use. Only a minority of existing meta-analyses suggest mortality benefits and reduction in IPN. The majority of existing guidelines do not recommend the use of PABs in AP. More research is required to make more definitive conclusions. Currently, PAB should only be administered after multidisciplinary discussions led by pancreatology experts.