Background/Objectives: Prophylactic antibiotics (PAB) are being still widely used for treatment of acute pancreatitis (AP) despite trials showing no firm evidence of efficacy. We aimed to evaluate effects of PAB for AP in a meta-analysis and the need for further research by trial sequential analysis (TSA). Methods: Medline, Scopus and Web of Science were searched for randomized clinical trials. Primary outcomes were all infections and mortality. Secondary outcomes comprised infected pancreatic necrosis (IPN), specific infections, organ failure, surgical interventions, and length of hospital stay. Results: Twenty-one trials with 1383 pts were included. PAB were received by 703 pts, while 680 were controls. Mortality was similar with RR 0.85 (95% CI 0.66–1.10). Infections were significantly reduced (RR 0.60; 95% CI 0.49–0.74), mainly due to decreased risk of sepsis (RR 0.43; 95% CI 0.25–0.73) and urinary tract infections (RR 0.46; 95% CI 0.25–0.86). No significant reduction for IPN was shown (RR 0.81; 95% CI 0.63–1.04). Length of hospital stay was diminished by MD −6.65 (95% CI −8.86 to −4.43) days. TSA for all infections showed that the cumulative Z score crossed both conventional and monitoring boundaries at 526 pts from a heterogeneity-corrected required information size of 1113 pts based on a 40% incidence of infections in the control group, RRR of 30%, alpha 5%, beta 20%, and heterogeneity 56%. Conclusions: PABs decrease the rate of infections in AP, mainly due to RRR of extra-pancreatic infections, requiring no further research. No significant effect is shown on IPN and mortality, although firmer evidence is needed.